PubAnnotation

http://purl.obolibrary.org/obo/GO_0002449

denotes

cell-mediated immune

T767

http://purl.obolibrary.org/obo/GO_0002456

denotes

cell-mediated immune

T768

http://purl.obolibrary.org/obo/GO_0019724

denotes

cell-mediated immune

T769

http://purl.obolibrary.org/obo/GO_0002228

denotes

cell-mediated immune

T771

http://purl.obolibrary.org/obo/GO_0001909

denotes

cell-mediated immune

T770

354-384

http://purl.obolibrary.org/obo/GO_0002443

denotes

cell-mediated immune responses

T755

368-384

http://purl.obolibrary.org/obo/GO_0006955

denotes

immune responses

T757

417-426

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T772

458-476

http://purl.obolibrary.org/obo/GO_0008283

denotes

cell proliferation

T773

478-497

http://purl.obolibrary.org/obo/GO_0002377

denotes

antibody production

T774

503-509

http://purl.obolibrary.org/obo/GO_0007613

denotes

memory

T775

512-528

http://purl.obolibrary.org/obo/GO_0048468

denotes

cell development

T776

517-528

http://purl.obolibrary.org/obo/GO_0032502

denotes

development

T777

561-570

http://purl.obolibrary.org/obo/GO_0009058

denotes

formation

T778

561-584

http://purl.obolibrary.org/obo/GO_0032800

denotes

formation of a receptor

T779

618-637

http://purl.obolibrary.org/obo/GO_0051092

denotes

activation of NF-κB

T782

http://purl.obolibrary.org/obo/GO_0034199

denotes

activated protein kinases

T783

http://purl.obolibrary.org/obo/GO_0032147

denotes

activated protein kinases

T784

http://purl.obolibrary.org/obo/GO_0030295

denotes

activated protein kinases

T785

http://purl.obolibrary.org/obo/GO_0032111

denotes

activated protein kinases

T758

683-692

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T759

752-761

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T760

838-847

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T786

1125-1147

http://purl.obolibrary.org/obo/GO_0023035

denotes

CD40 signaling pathway

T788

1125-1147

http://purl.obolibrary.org/obo/GO_2000348

denotes

CD40 signaling pathway

T761

1130-1139

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T790

1130-1147

http://purl.obolibrary.org/obo/GO_0007165

denotes

signaling pathway

T762

1187-1196

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T792

1386-1399

http://purl.obolibrary.org/obo/GO_0006351

denotes

transcription

T780

1477-1496

http://purl.obolibrary.org/obo/GO_0051092

denotes

activation of NF-κB

T763

1575-1584

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T781

1672-1688

http://purl.obolibrary.org/obo/GO_0051092

denotes

NF-κB activation

T793

1745-1753

http://purl.obolibrary.org/obo/GO_0007349

denotes

cellular

T764

1769-1778

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T787

1832-1854

http://purl.obolibrary.org/obo/GO_0023035

denotes

CD40 signaling pathway

T789

1832-1854

http://purl.obolibrary.org/obo/GO_2000348

denotes

CD40 signaling pathway

T765

1837-1846

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T791

1837-1854

http://purl.obolibrary.org/obo/GO_0007165

denotes

signaling pathway

T2312

1875-1884

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T2324

http://purl.obolibrary.org/obo/GO_0002449

denotes

cell-mediated immune

T2325

http://purl.obolibrary.org/obo/GO_0002456

denotes

cell-mediated immune

T2326

http://purl.obolibrary.org/obo/GO_0019724

denotes

cell-mediated immune

T2327

http://purl.obolibrary.org/obo/GO_0002228

denotes

cell-mediated immune

T2329

http://purl.obolibrary.org/obo/GO_0001909

denotes

cell-mediated immune

T2328

2036-2066

http://purl.obolibrary.org/obo/GO_0002443

denotes

cell-mediated immune responses

T2330

2050-2066

http://purl.obolibrary.org/obo/GO_0006955

denotes

immune responses

T2313

2087-2096

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T2314

2267-2276

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T2332

http://purl.obolibrary.org/obo/GO_0034199

denotes

activated protein kinases

T2334

http://purl.obolibrary.org/obo/GO_0032147

denotes

activated protein kinases

T2336

http://purl.obolibrary.org/obo/GO_0030295

denotes

activated protein kinases

T2338

http://purl.obolibrary.org/obo/GO_0032111

denotes

activated protein kinases

T2340

2339-2352

http://purl.obolibrary.org/obo/GO_0006351

denotes

transcription

T2331

2443-2459

http://purl.obolibrary.org/obo/GO_0006955

denotes

immune responses

T2315

2503-2512

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T2341

2503-2521

http://purl.obolibrary.org/obo/GO_0007165

denotes

signaling pathways

T2316

2663-2672

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T2344

2894-2904

http://purl.obolibrary.org/obo/GO_0065007

denotes

regulation

T2346

2894-2922

http://purl.obolibrary.org/obo/GO_2000348

denotes

regulation of CD40 signaling

T2317

2913-2922

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T2348

http://purl.obolibrary.org/obo/GO_0004842

denotes

E3

T2349

http://purl.obolibrary.org/obo/GO_0019787

denotes

E3

T2350

http://purl.obolibrary.org/obo/GO_0061630

denotes

E3

T2351

http://purl.obolibrary.org/obo/GO_0061659

denotes

E3

T2352

http://purl.obolibrary.org/obo/GO_0061660

denotes

E3

T2353

http://purl.obolibrary.org/obo/GO_0061661

denotes

E3

T2354

http://purl.obolibrary.org/obo/GO_0061662

denotes

E3

T2355

http://purl.obolibrary.org/obo/GO_0061663

denotes

E3

T2356

http://purl.obolibrary.org/obo/GO_0061664

denotes

E3

T2357

http://purl.obolibrary.org/obo/GO_0061665

denotes

E3

T2358

http://purl.obolibrary.org/obo/GO_0061666

denotes

E3

T2359

http://purl.obolibrary.org/obo/GO_0061667

denotes

E3

T2345

3214-3224

http://purl.obolibrary.org/obo/GO_0065007

denotes

regulation

T2318

3323-3332

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T2319

3393-3402

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T2342

3393-3411

http://purl.obolibrary.org/obo/GO_0007165

denotes

signaling pathways

T2360

3393-3414

http://purl.obolibrary.org/obo/GO_0007214

denotes

signaling pathways [4

T2361

3543-3556

http://purl.obolibrary.org/obo/GO_0000209

denotes

polyubiquitin

T2347

3768-3790

http://purl.obolibrary.org/obo/GO_2000348

denotes

CD40 signaling pathway

T2362

3768-3790

http://purl.obolibrary.org/obo/GO_0023035

denotes

CD40 signaling pathway

T2320

3773-3782

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T2363

3826-3845

http://purl.obolibrary.org/obo/GO_0051092

denotes

activation of NF-κB

T2321

3865-3874

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T2322

4056-4065

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T2366

4394-4411

http://purl.obolibrary.org/obo/GO_0045190

denotes

isotype switching

T2364

4488-4507

http://purl.obolibrary.org/obo/GO_0051092

denotes

activation of NF-κB

T2367

4516-4547

http://purl.obolibrary.org/obo/GO_0016909

denotes

stress-activated protein kinase

T2368

4516-4547

http://purl.obolibrary.org/obo/GO_0007254

denotes

stress-activated protein kinase

T2333

http://purl.obolibrary.org/obo/GO_0034199

denotes

activated protein kinase

T2335

http://purl.obolibrary.org/obo/GO_0032147

denotes

activated protein kinase

T2337

http://purl.obolibrary.org/obo/GO_0030295

denotes

activated protein kinase

T2339

http://purl.obolibrary.org/obo/GO_0032111

denotes

activated protein kinase

T2369

4523-4549

http://purl.obolibrary.org/obo/GO_1990051

denotes

activated protein kinase c

T2370

4533-4549

http://purl.obolibrary.org/obo/GO_0004697

denotes

protein kinase c

T2371

4533-4549

http://purl.obolibrary.org/obo/GO_0042313

denotes

protein kinase c

T2372

4533-4549

http://purl.obolibrary.org/obo/GO_0070528

denotes

protein kinase c

T2373

4562-4565

http://purl.obolibrary.org/obo/GO_0004705

denotes

JNK

T2365

4631-4647

http://purl.obolibrary.org/obo/GO_0051092

denotes

NF-κB activation

T8279

4668-13422

http://purl.obolibrary.org/obo/GO_0008384

denotes

IκB kinase (IKK) complex with CD40 was undetectable in HOIP-deficient cells. Together, our results indicate that HOIP plays a critical role in the activation of signaling pathways that regulate cellular responses to CD40 engagement. Results Generation of HOIP-deficient B cells via targeted disruption of Rnf31, the gene encoding HOIP In our previous study, we demonstrated that HOIP is recruited to the CD40 signaling complex in two mouse B cell lines [6]. Similar results were obtained with mouse splenocytes, indicating that the interaction of CD40 with HOIP is not limited to transformed B cell lines (unpublished observations). We also found that the recruitment of HOIP to CD40 was TRAF2-dependent and that overexpression of a truncated HOIP mutant partially inhibited CD40-mediated NF-κB activation. These results support the hypothesis that HOIP plays a role in CD40 signal transduction. To further define the role and evaluate the importance of HOIP in CD40 signaling, we used somatic cell gene targeting to disrupt the gene encoding HOIP in the mouse B cell line A20.2J. This cell line has been particularly useful in the characterization of CD40 signaling mechanisms due to the relative ease with which its genome can be modified by homologous recombination [7], [8], [9]. We used a targeting vector capable of undergoing homologous recombination with Rnf31 (the gene encoding HOIP) to disrupt the coding sequence of the gene in exon 5 (Fig. 1A). Following introduction of the vector, the neomycin-resistant clones that arose were screened by PCR amplification of genomic DNA to identify cells containing a disrupted Rnf31 allele. To remove the selectable marker gene cassette from the disrupted Rnf31 allele, recombinant cell lines were transiently transfected with a plasmid that encodes Cre recombinase. This step allowed us to perform a second round of targeting and drug selection, generating cells in which both copies of Rnf31 were disrupted. Two independent clonal cell lines were chosen for further analysis. HOIP protein expression was undetectable in both cell lines, as determined by Western blot analysis of cell lysates (Fig. 1B), demonstrating that the targeting process was successful. In the text that follows, the two gene-targeted cell lines are referred to as HOIP-deficient cells. 10.1371/journal.pone.0023061.g001 Figure 1 HOIP gene targeting. (A) Regions of Rnf31 gene sequence (bottom) used in the HOIP gene targeting vector (top) are shown. Arrows (F and R) indicate approximate positions of sequences homologous to oligonucleotides used for PCR-mediated detection of homologous recombination. Homologous recombination of the vector with Rnf31 resulted in a small chromosomal deletion and the in-frame insertion of neomycin phosphotransferase (NeoR) into the amino-terminal HOIP coding sequence. A diphtheria toxin (DT) cassette in the vector facilitates the negative selection of cells in which random chromosomal insertion of the vector takes place. LoxP sequences allow the Cre-mediated deletion of the NeoR coding sequence. The SV40pA sequence helps to ensure disruption of gene expression after deletion of the NeoR sequence. (B) Anti-HOIP and anti-FLAG Western blots of cell lysates from A20.2J cells and HOIP-deficient (HOIP-/-) clones. A partial decrease in HOIP protein expression is evident in cells following disruption of one copy of Rnf31 (HOIP−/+). HOIP expression in clones reconstituted with an empty retroviral vector (pMIP) or a retroviral vector encoding FLAG-tagged HOIP is also shown. Approximate molecular weight of HOIP is 120 kD. To enable us to confirm that any signaling or functional defects observed in HOIP-deficient cells were due to disruption of the Rnf31 gene, both HOIP-deficient cell lines were transduced with a retrovirus encoding FLAG-tagged wild-type HOIP, thus restoring HOIP protein expression (Fig. 1B). These cells are referred to as HOIP-reconstituted cells. In the experiments that follow, responses by these cells were compared to those of A20.2J cells and HOIP-deficient cells transduced with a retroviral vector (pMIP) lacking a cDNA insert (empty vector). HOIP is required for CD40-mediated CD80 upregulation and activation of germline epsilon transcription Engagement of CD40 on B cells upregulates expression of CD80 [10], a cell surface protein that promotes activation of T cells interacting with B cells and other APC. To begin evaluating potential contributions of HOIP to CD40 signaling, we assayed the upregulation of CD80 induced by engagement of CD40 on parental A20.2J, HOIP-deficient, and HOIP-reconstituted cells (Fig. 2). Compared to the parental cell line, the CD40-stimulated upregulation of CD80 was dramatically reduced in all HOIP-deficient cells tested. In contrast, upregulation of CD80 was restored in HOIP-reconstituted cells, confirming that the defect in CD80 upregulation in the HOIP-deficient cells was due to the disruption of Rnf31. 10.1371/journal.pone.0023061.g002 Figure 2 CD40-mediated CD80 upregulation is defective in HOIP-deficient cells. Cells were incubated for 72 hrs with an isotype control antibody (left) or anti-CD40 antibody (right) and then stained for expression of CD80 (filled profiles indicate staining with anti-CD80 antibody; open profiles are staining with an isotype control antibody). Transduction of both HOIP-deficient (HOIP-/-) clones with a retrovirus encoding FLAG-HOIP reversed defective CD80 upregulation, while transduction with an empty vector (pMIP) did not. Similar results were obtained in a second experiment. CD40 signals in B cells can also contribute to the activation of DNA recombination in the immunoglobulin heavy chain locus [11], [12]. This process, known as immunoglobulin class switching (or isotype switching), allows B cells, initially expressing IgM, to switch to IgA, IgG, or IgE depending on the class of antibody most appropriate for a particular immune response. Switching to IgE can be induced by the combination of IL-4 and CD40 signals. The gene rearrangement necessary for IgE production is preceded by the production of non-coding RNA transcripts from germline sequences in the IgE heavy chain locus [13]. To determine whether HOIP is required in the initiation of the class switching process, the relevant B cell lines were stimulated through CD40 in the presence of IL-4 and tested for production of germline epsilon (GLε) transcripts (Fig. 3). Anti-CD40 antibody stimulation alone or together with IL-4 induced GLε transcription in parental A20.2J cells as expected. In contrast, only low levels of GLε expression were detected in HOIP-deficient cells stimulated with either anti-CD40 antibody alone or anti-CD40 and IL-4. Normal levels of GLε expression were induced in HOIP-reconstituted cells stimulated with anti-CD40 antibody alone or together with IL-4. Collectively, these data demonstrate that HOIP has a critical role in cellular responses to CD40 signaling. 10.1371/journal.pone.0023061.g003 Figure 3 GLε transcription is defective in CD40-stimulated HOIP-deficient cells. A20.2J and HOIP-deficient cells transduced with an empty retroviral vector (A20.2J + pMIP and HOIP-/- + pMIP, respectively), or HOIP-deficient cells transduced with a HOIP-encoding retrovirus (HOIP-/- + HOIP) were cultured overnight with agonistic anti-CD40 or an isotype control antibody (iso), with or without IL-4. RNA was isolated from the cells, reverse-transcribed, and then subjected to quantitative PCR to determine levels of GLε transcripts. Results were normalized to the levels of Hprt1 transcripts in each sample. Symbols indicate the values from duplicate cultures (a line indicates the mean of the two values). Similar results were obtained in a second experiment and in an additional experiment with a second HOIP-deficient clone. HOIP mediates CD40-stimulated NF-κB and JNK activation The results described above show that HOIP plays an important role in CD40-mediated effector functions of B cells. It follows that HOIP is likely a key mediator of CD40 signaling. To test this hypothesis, we stimulated A20.2J and HOIP-deficient cells with CD154 (CD40 ligand) expressed by HI5 insect cells [7], [8] and measured activation of the NF-κB and JNK pathways, two of the major transcriptional regulators activated by CD40 [4]. Cell-associated CD154 was used as the stimulus in these experiments as it typically provides more robust, and therefore more readily detected, activation signals than does anti-CD40 antibody. Activation of the canonical NF-κB pathway is initiated with the phosphorylation of IκB proteins by the IκB kinase complex (IKK). In resting cells, IκB proteins are responsible for sequestering NF-κB subunits in the cytoplasm. Phosphorylation by the IKK

T2374

4680-4683

http://purl.obolibrary.org/obo/GO_0008384

denotes

IKK

T2375

http://purl.obolibrary.org/obo/GO_0009736

denotes

activation of signaling pathways

T2376

http://purl.obolibrary.org/obo/GO_0033211

denotes

activation of signaling pathways

T2377

http://purl.obolibrary.org/obo/GO_1901186

denotes

activation of signaling pathways

T2378

http://purl.obolibrary.org/obo/GO_1902204

denotes

activation of signaling pathways

T2379

http://purl.obolibrary.org/obo/GO_0009873

denotes

activation of signaling pathways

T2380

http://purl.obolibrary.org/obo/GO_0038084

denotes

activation of signaling pathways

T2381

http://purl.obolibrary.org/obo/GO_1900236

denotes

activation of signaling pathways

T2382

http://purl.obolibrary.org/obo/GO_1902046

denotes

activation of signaling pathways

T2383

http://purl.obolibrary.org/obo/GO_1902843

denotes

activation of signaling pathways

T2384

http://purl.obolibrary.org/obo/GO_1903265

denotes

activation of signaling pathways

T2323

4829-4838

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T2343

4829-4847

http://purl.obolibrary.org/obo/GO_0007165

denotes

signaling pathways

T2385

4862-4870

http://purl.obolibrary.org/obo/GO_0007349

denotes

cellular

T3835

5079-5088

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T3839

5545-5564

http://purl.obolibrary.org/obo/GO_0007165

denotes

signal transduction

T3840

5552-5564

http://purl.obolibrary.org/obo/GO_0009293

denotes

transduction

T3836

5637-5646

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T3837

5827-5836

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T15254

7785-7800

http://purl.obolibrary.org/obo/GO_0010467

denotes

gene expression

T3838

8296-8305

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T5069

8903-8916

http://purl.obolibrary.org/obo/GO_0006351

denotes

transcription

T5071

8986-9006

http://purl.obolibrary.org/obo/GO_0033580

denotes

cell surface protein

T5072

8986-9006

http://purl.obolibrary.org/obo/GO_0034394

denotes

cell surface protein

T5073

8986-9006

http://purl.obolibrary.org/obo/GO_0033575

denotes

cell surface protein

T5074

9143-9152

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T15595

9999-10011

http://purl.obolibrary.org/obo/GO_0009293

denotes

Transduction

T15596

10133-10145

http://purl.obolibrary.org/obo/GO_0009293

denotes

transduction

T5076

10290-10321

http://purl.obolibrary.org/obo/GO_0045911

denotes

activation of DNA recombination

T5077

10304-10321

http://purl.obolibrary.org/obo/GO_0006310

denotes

DNA recombination

T5078

10412-10427

http://purl.obolibrary.org/obo/GO_0045190

denotes

class switching

T5080

http://purl.obolibrary.org/obo/GO_0048290

denotes

class switching (or isotype

T5081

http://purl.obolibrary.org/obo/GO_0048292

denotes

class switching (or isotype

T5082

http://purl.obolibrary.org/obo/GO_0048289

denotes

class switching (or isotype

T5083

http://purl.obolibrary.org/obo/GO_0048291

denotes

class switching (or isotype

T5079

10418-10439

http://purl.obolibrary.org/obo/GO_0045190

denotes

switching (or isotype

T5084

10593-10608

http://purl.obolibrary.org/obo/GO_0006955

denotes

immune response

T5070

11170-11183

http://purl.obolibrary.org/obo/GO_0006351

denotes

transcription

T5085

11585-11593

http://purl.obolibrary.org/obo/GO_0007349

denotes

cellular

T5075

11612-11621

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T16041

11671-11684

http://purl.obolibrary.org/obo/GO_0006351

denotes

transcription

T6097

12526-12529

http://purl.obolibrary.org/obo/GO_0004705

denotes

JNK

T6103

12710-12719

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T6105

12869-12892

http://purl.obolibrary.org/obo/GO_0051092

denotes

activation of the NF-κB

T6098

12897-12900

http://purl.obolibrary.org/obo/GO_0004705

denotes

JNK

T6107

12928-12943

http://purl.obolibrary.org/obo/GO_0006351

denotes

transcriptional

T6104

13132-13139

http://purl.obolibrary.org/obo/GO_0023052

denotes

signals

T6108

13234-13249

http://purl.obolibrary.org/obo/GO_0016310

denotes

phosphorylation

T6111

13234-13256

http://purl.obolibrary.org/obo/GO_0007252

denotes

phosphorylation of IκB

T6112

13293-13296

http://purl.obolibrary.org/obo/GO_0008384

denotes

IKK

T6114

13350-13362

http://purl.obolibrary.org/obo/GO_0051235

denotes

sequestering

T6113

13419-13422

http://purl.obolibrary.org/obo/GO_0008384

denotes

IKK

T6115

13443-13470

http://purl.obolibrary.org/obo/GO_0016567

denotes

proteins for ubiquitination

T6116

13475-13486

http://purl.obolibrary.org/obo/GO_0009056

denotes

degradation

T6118

13537-13552

http://purl.obolibrary.org/obo/GO_0010467

denotes

gene expression

T6109

13568-13583

http://purl.obolibrary.org/obo/GO_0016310

denotes

phosphorylation

T6117

13588-13599

http://purl.obolibrary.org/obo/GO_0009056

denotes

degradation

T6119

http://purl.obolibrary.org/obo/GO_0034199

denotes

activated protein kinase

T6120

http://purl.obolibrary.org/obo/GO_0032147

denotes

activated protein kinase

T6121

http://purl.obolibrary.org/obo/GO_0030295

denotes

activated protein kinase

T6122

http://purl.obolibrary.org/obo/GO_0032111

denotes

activated protein kinase

T6099

13785-13788

http://purl.obolibrary.org/obo/GO_0004705

denotes

JNK

T6100

13844-13847

http://purl.obolibrary.org/obo/GO_0004705

denotes

JNK

T6110

13911-13926

http://purl.obolibrary.org/obo/GO_0016310

denotes

phosphorylation

T6101

13951-13954

http://purl.obolibrary.org/obo/GO_0004705

denotes

JNK

T6106

13969-13988

http://purl.obolibrary.org/obo/GO_0051092

denotes

activation of NF-κB

T6102

13993-13996

http://purl.obolibrary.org/obo/GO_0004705

denotes

JNK

T16565

14202-14221

http://purl.obolibrary.org/obo/GO_0051092

denotes

activation of NF-κB

T16566

14226-14229

http://purl.obolibrary.org/obo/GO_0004705

denotes

JNK

T16570

14282-14291

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T16567

14830-14833

http://purl.obolibrary.org/obo/GO_0004705

denotes

JNK

T16568

14899-14902

http://purl.obolibrary.org/obo/GO_0004705

denotes

JNK

T16569

14923-14926

http://purl.obolibrary.org/obo/GO_0004705

denotes

JNK

T8281

15311-15326

http://purl.obolibrary.org/obo/GO_0001775

denotes

cell activation

T8282

15331-15340

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T8283

15451-15460

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T8284

15551-15560

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T8290

15993-16002

http://purl.obolibrary.org/obo/GO_0006915

denotes

apoptosis

T8291

15993-16002

http://purl.obolibrary.org/obo/GO_0097194

denotes

apoptosis

T8285

16148-16157

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T8292

16743-16751

http://purl.obolibrary.org/obo/GO_0007349

denotes

cellular

T8293

http://purl.obolibrary.org/obo/GO_0043687

denotes

post-translational modification

T8295

http://purl.obolibrary.org/obo/GO_1901873

denotes

post-translational modification

T8297

http://purl.obolibrary.org/obo/GO_1901874

denotes

post-translational modification

T8299

http://purl.obolibrary.org/obo/GO_1901875

denotes

post-translational modification

T17748

16975-16978

http://purl.obolibrary.org/obo/GO_0008384

denotes

IKK

T17750

17003-17012

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T17749

18327-18330

http://purl.obolibrary.org/obo/GO_0008384

denotes

IKK

T17751

19081-19092

http://purl.obolibrary.org/obo/GO_0016791

denotes

phosphatase

T17752

19176-19187

http://purl.obolibrary.org/obo/GO_0016791

denotes

phosphatase

T8286

19471-19480

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T8287

19526-19535

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T8288

19636-19645

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T8280

20302-20305

http://purl.obolibrary.org/obo/GO_0008384

denotes

IKK

T8289

20489-20498

http://purl.obolibrary.org/obo/GO_0023052

denotes

signaling

T8301

21441-21452

http://purl.obolibrary.org/obo/GO_0016791

denotes

phosphatase

T8302

21769-21780

http://purl.obolibrary.org/obo/GO_0016791

denotes

phosphatase

T8303

21890-21905

http://purl.obolibrary.org/obo/GO_0016310

denotes

phosphorylation

T8294

http://purl.obolibrary.org/obo/GO_0043687

denotes

post-translational modifications

T8296

http://purl.obolibrary.org/obo/GO_1901873

denotes

post-translational modifications

T8298

http://purl.obolibrary.org/obo/GO_1901874

denotes

post-translational modifications

T8300

http://purl.obolibrary.org/obo/GO_1901875

denotes

post-translational modifications

T11273

22168-22175

http://purl.obolibrary.org/obo/GO_0023052

denotes

signals

T11280

22241-22249

http://purl.obolibrary.org/obo/GO_0007349

denotes

cellular

T11282

22318-22327

http://purl.obolibrary.org/obo/GO_0009058

denotes

synthesis

T11284

22450-22484

http://purl.obolibrary.org/obo/GO_0016064

denotes

antibody-mediated immune responses

T11285

22450-22484

http://purl.obolibrary.org/obo/GO_0002455

denotes

antibody-mediated immune responses

T11286

22459-22484

http://purl.obolibrary.org/obo/GO_0002443

denotes

mediated immune responses

T11287

22468-22484

http://purl.obolibrary.org/obo/GO_0006955

denotes

immune responses

T11289

22575-22597

http://purl.obolibrary.org/obo/GO_0023035

denotes

CD40 signaling pathway

T11291

22575-22597

http://purl.obolibrary.org/obo/GO_2000348

denotes

CD40 signaling pathway

T11293

22580-22597

http://purl.obolibrary.org/obo/GO_0007165

denotes

signaling pathway

T11296

22663-22666

http://purl.obolibrary.org/obo/GO_0008384

denotes

IKK

T11300

22719-22738

http://purl.obolibrary.org/obo/GO_0051092

denotes

activation of NF-κB

T11304

22844-22847

http://purl.obolibrary.org/obo/GO_0004705

denotes

JNK

T11290

22974-22996

http://purl.obolibrary.org/obo/GO_0023035

denotes

CD40 signaling pathway

T11292

22974-22996

http://purl.obolibrary.org/obo/GO_2000348

denotes

CD40 signaling pathway

T11294

22979-22996

http://purl.obolibrary.org/obo/GO_0007165

denotes

signaling pathway

T11281

23045-23053

http://purl.obolibrary.org/obo/GO_0007349

denotes

cellular

T11308

http://purl.obolibrary.org/obo/GO_0002922

denotes

humoral immune responses

T11309

http://purl.obolibrary.org/obo/GO_0006959

denotes

humoral immune responses

T11310

http://purl.obolibrary.org/obo/GO_0002920

denotes

humoral immune responses

T11311

http://purl.obolibrary.org/obo/GO_0002921

denotes

humoral immune responses

T11288

23066-23082

http://purl.obolibrary.org/obo/GO_0006955

denotes

immune responses

T11312

23142-23152

http://purl.obolibrary.org/obo/GO_0065007

denotes

regulation

T11314

23142-23173

http://purl.obolibrary.org/obo/GO_0002682

denotes

regulation of the immune system

T11315

23397-23410

http://purl.obolibrary.org/obo/GO_0000209

denotes

polyubiquitin

T11301

23518-23537

http://purl.obolibrary.org/obo/GO_0051092

denotes

activation of NF-κB

T11320

23963-23978

http://purl.obolibrary.org/obo/GO_0006351

denotes

transcriptional

T11321

24003-24018

http://purl.obolibrary.org/obo/GO_0016310

denotes

phosphorylation

T11297

24183-24186

http://purl.obolibrary.org/obo/GO_0008384

denotes

IKK

T11298

24332-24335

http://purl.obolibrary.org/obo/GO_0008384

denotes

IKK

T11299

24420-24423

http://purl.obolibrary.org/obo/GO_0008384

denotes

IKK

T11322

http://purl.obolibrary.org/obo/GO_0004842

denotes

ubiquitin ligase activity

T11324

http://purl.obolibrary.org/obo/GO_0050372

denotes

ubiquitin ligase activity

T11326

http://purl.obolibrary.org/obo/GO_1904666

denotes

ubiquitin ligase activity

T11328

http://purl.obolibrary.org/obo/GO_1990757

denotes

ubiquitin ligase activity

T11330

http://purl.obolibrary.org/obo/GO_1904668

denotes

ubiquitin ligase activity

T11332

http://purl.obolibrary.org/obo/GO_0061630

denotes

ubiquitin ligase activity

T11334

http://purl.obolibrary.org/obo/GO_1904667

denotes

ubiquitin ligase activity

T11336

http://purl.obolibrary.org/obo/GO_0034450

denotes

ubiquitin ligase activity

T11338

24464-24479

http://purl.obolibrary.org/obo/GO_0016874

denotes

ligase activity

T11316

24587-24600

http://purl.obolibrary.org/obo/GO_0000209

denotes

polyubiquitin

T11283

24646-24655

http://purl.obolibrary.org/obo/GO_0009058

denotes

formation

T11317

24666-24679

http://purl.obolibrary.org/obo/GO_0000209

denotes

polyubiquitin

T11323

http://purl.obolibrary.org/obo/GO_0004842

denotes

ubiquitin ligase activity

T11325

http://purl.obolibrary.org/obo/GO_0050372

denotes

ubiquitin ligase activity

T11327

http://purl.obolibrary.org/obo/GO_1904666

denotes

ubiquitin ligase activity

T11329

http://purl.obolibrary.org/obo/GO_1990757

denotes

ubiquitin ligase activity

T11331

http://purl.obolibrary.org/obo/GO_1904668

denotes

ubiquitin ligase activity

T11333

http://purl.obolibrary.org/obo/GO_0061630

denotes

ubiquitin ligase activity

T11335

http://purl.obolibrary.org/obo/GO_1904667

denotes

ubiquitin ligase activity

T11337