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adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity.\r\nHideki Hara, Kohsuke Tsuchiya, Ikuo Kawamura, Rendong Fang, Eduardo Hernandez-Cuellar, Yanna Shen, Junichiro Mizuguchi, Edina Schweighoffer, Victor Tybulewicz, Masao Mitsuyama\r\nNature Immunology, 14, 1247-1255 (2013)\r\n\r\n〈要 約〉\r\n　感染などに対する自然免疫による生体の炎症応答に重要なインフラマソームにおいて，ASCはカスパーゼ1の活性化において必須のアダプタータンパク質である．しかしながら，ASCの活性化の機構については十分に解明されていなかった．この研究では，ASCに依存したインフラマソームの形成によるインターロイキン18の成熟，および，インフラマソームとは別のタンパク質複合体であるASCスペックの形成を指標として，それらのシグナル伝達系について解析した．その結果，SykやJnkなどのキナーゼがASCスペックの形成において必須であり，その下流においてASCのTyr144のリン酸化が起こること，さらに，このリン酸化がカスパーゼ1の活性化において重要であることが見い出された．この発見により，感染防御にかぎらず，過剰なインフラマソームの形成により病態を形成する炎症性疾患へのアプローチも可能になると考えられた．\r\n\r\nはじめに\r\n　自然免疫は下等生物から高等生物にいたるまで共通して保存された生体防御機構であり，多数のパターン認識受容体が自然免疫応答において中心的な役割を担う．NLRP3，AIM2，NLRC4などのパターン認識受容体は，刺激となる特定の因子（アゴニスト）を認識すると構造変化を起こしてASCやカスパーゼ1などのタンパク質と会合し，インフラマソームとよばれるタンパク質複合体を形成する1)（図1）．インフラマソームにおいてはタンパク質分解酵素であるカスパーゼ1が活性化され，活性型となったカスパーゼ1がインターロイキン1などの炎症性サイトカインの成熟および分泌を誘導することにより炎症が起こる2)．\r\n　インフラマソームの形成は各種の病原微生物の感染により誘導されるが，それにもとづく炎症応答は，多くの場合，宿主における感染防御に効果的に作用する3)．また，インフラマソームは腸内細菌叢の制御および腸管上皮のバリアの保護にもはたらき，腸管における恒常性の維持に寄与するとも考えられている．これに対して，インフラマソームが宿主にとり不都合な結果を誘導する負の側面も知られている．刺激となる因子の種類により，過剰なインフラマソームの形成が不適切かつ持続した炎症を惹起し，動脈硬化，痛風，2型糖尿病，アルツハイマー病など，各種の疾患の発症にかかわると考えられている4,5)．また，ある種の自己炎症疾患の発症にはインフラマソームを構成するタンパク質の変異が関与することも示唆されている．そのため，インフラマソームの形成または活性化の制御機構を解明することは，病態の機構への理解を深め疾患へのアプローチに貢献すると期待される．\r\n　インフラマソームの重要な構成タンパク質のひとつであるASCは，インフラマソームにおいてはパターン認識受容体とカスパーゼ1との会合を助けるアダプタータンパク質としてはたらくが，インフラマソームが形成される際にはASCそれ自体が凝集してASCスペックとよばれる別のタンパク質複合体を形成する（図1）．このASCスペックはインフラマソームと同様にカスパーゼ1をリクルートしその活性化の場としてはたらくことから，インフラマソームを介した炎症応答において重要な役割をはたすと考えられる6)．しかしながら，ASCスペックの形成がどのような機序により誘導されるかについてはこれまで明らかにされていなかった．\r\n　そこで，この研究においては，ASCの関与するインフラマソームの形成におけるシグナル伝達系について解明するため，NLRPインフラマソームおよびAIM2インフラマソームにおいて形成されるASCスペック，および，カスパーゼ1の活性化により誘導されるインターロイキン18あるいはインターロイキン1βの成熟を指標として7)，解析を行った．\r\n\r\n1．各種のシグナル阻害剤の影響\r\n　インフラマソームの形成や活性化にかかわるシグナル伝達系を探索する目的で，各種のシグナル阻害剤のインフラマソームへの影響を調べた．その結果，キナーゼであるSykおよびJNKがインフラマソームを介したカスパーゼ1の活性化および炎症性サイトカインの産生にかかわることがわかった．SykおよびJNKはどのようにインフラマソームの活性にかかわるのか，さまざまな可能性を検討したところ，ASCスペックの形成がこれらのキナーゼに依存していることがわかった．すなわち，SykおよびJNKはASCスペックの形成を制御することによりインフラマソームを介した炎症応答に寄与していることが示唆された．\r\n\r\n2．インフラマソームを構成するタンパク質のリン酸化\r\n　SykおよびJNKがどのような機序によりASCスペックの形成を制御しているのか検討した．SykおよびJNKはキナーゼであることから，インフラマソームを構成するタンパク質のリン酸化が関与している可能性が考えられた．そこで，インフラマソームが形成されるときリン酸化されるタンパク質を探索した結果，ASCがSykおよびJNKに依存してリン酸化されることが明らかになった．さらに，ASCの144番目のチロシン残基がそのリン酸化部位であることも見い出した．さらに，このTyr144に変異を導入したASCを用いた実験により，この残基がASCスペックの形成や炎症性サイトカインの産生の誘導に重要であることも確認された．これらの実験の結果から，SykおよびJNKに依存したASCのTyr144リン酸化がASCスペックの形成において重要な役割をはたし，インフラマソームを介した炎症応答の誘導にはたらくことが示された（図2）．\r\n\r\n3．in vivoにおけるSykおよびJNKの関与\r\n　in vitroにおける実験で明らかになったSykおよびJNKのインフラマソームの形成への関与は，in vivoにおいても再現できるかどうか，マウスの腹膜炎モデルを用いて検討した．マウスの腹腔に尿酸結晶を投与すると，インフラマソームに依存して好中球の浸潤の起こることが知られている8)．そこで，SykあるいはJNKを欠損したマウスを作出し，尿酸結晶を投与したのち，腹腔内に浸潤した浸潤した細胞の数および浸潤した細胞画分の比率を野生型のマウスと比較した．その結果，SykあるいはJNKの欠損により好中球の浸潤の誘導は有意に減少するという結果が得られた．すなわち，SykおよびJNKは生体においてもインフラマソームを介した炎症応答の制御にはたらくことが確認された．\r\n\r\nおわりに\r\n　これまで，ASCスペックの形成は単純にASCの凝集現象と考えられてきたが，今回の研究において，SykおよびJNKによるASCのリン酸化がその過程に重要な役割をはたすことがはじめて明らかになった．今回の研究により得られた結果を基盤として，ASCのリン酸化がASCスペックの形成にはたらく詳細な分子機構について明らかにしていく必要があるだろう．また，キナーゼによるタンパク質のリン酸化反応は化合物による制御が比較的容易であることから，ASCのリン酸化を特異的に阻害する化合物の探索あるいは設計により，インフラマソームを介した炎症応答の制御，ひいては，インフラマソームに関連する疾患の治療に応用することも期待できるだろう．既存の自己炎症疾患モデルマウスなどを用い，SykあるいはJNKの阻害が実際に症状を緩和するかどうか検討していきたい．\r\n\r\n〈文 献〉\r\n 1) Martinon, F., Mayor, A. \u0026 Tschopp, J.: The inflammasomes: guardians of the body. Annu. Rev. Immunol., 27, 229-265 (2009)\r\n 2) Dinarello, C. A.: Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol., 27, 519-550 (2009)\r\n 3) Fang, R., Tsuchiya, K., Kawamura, I. et al.: Critical roles of ASC inflammasomes in caspase-1 activation and host innate resistance to Streptococcus pneumoniae infection. J. Immunol., 187, 4890-4899 (2011)\r\n 4) Vandanmagsar, B., Youm, Y. H., Ravussin, A. et al.: The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med., 17, 179-188 (2011)\r\n 5) Davis, B. K., Wen, H. \u0026 Ting, J. P.: The inflammasome MLRs in immunity, inflammation, and associated diseases. Annu. Rev. Immunol., 29, 707-735 (2011)\r\n 6) Bryan, N. B., Dorfleutner, A., Rojanasakul, Y. et al.: Activation of inflammasomes requires intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain. J. Immunol., 182, 3173-3182 (2009)\r\n 7) Tsuchiya, K., Hara, H., Kawamura, K. et al.: Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes. J. Immunol., 185, 1186-1195 (2010)\r\n 8) Martinon, F., Petrilli, V., Mayor, A. et al.: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature, 440, 237-241 (2006)\r\n\r\n〈著者プロフィール〉\r\n原 英樹（Hideki Hara）\r\n略歴：2007年 京都大学大学院医学研究科 修了，2008年 同 助教を経て，2013年より米国Michigan大学 研究員．\r\n\r\n光山 正雄（Masao Mitsuyama）\r\n京都大学大学院総合生存学館 特定教授．\r\n\r\n〈図説明〉\r\n図1　インフラマソームおよびASCスペックの構造と形成\r\n図2　ASCのリン酸化によるASCスペックの形成の制御"}