The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis.
The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis.
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A20是一种与多种人类疾病相关的抗炎蛋白，但A20预防炎症性疾病的机制尚未完全确定。我们现在发现，A20缺陷型T细胞和成纤维细胞对半胱天冬酶非依赖性和RIPK 3依赖性坏死性凋亡敏感。整体RIPK 3缺陷显著挽救了A20缺陷小鼠的存活。A20缺陷细胞表现出RIPK 1-RIPK 3复合物的过度形成。RIPK 3在赖氨酸5（K5）处经历生理泛素化，并且这种泛素化事件支持RIPK 1-RIPK 3复合物的形成。A20的去泛素化基序的催化半胱氨酸是抑制RIPK 3泛素化和RIPK 1-RIPK 3复合物形成所必需的。这些研究将A20和RIPK 3泛素化与坏死性细胞死亡联系起来，并提出了A20可能预防炎症性疾病的新机制。
A20 is an anti-inflammatory protein linked to multiple human diseases, however the mechanisms by which A20 prevents inflammatory disease are incompletely defined. We now find that A20 deficient T cells and fibroblasts are susceptible to caspase independent and RIPK3 dependent necroptosis. Global RIPK3 deficiency significantly rescues the survival of A20 deficient mice. A20 deficient cells exhibit exaggerated formation of RIPK1-RIPK3 complexes. RIPK3 undergoes physiological ubiquitination at lysine 5 (K5), and this ubiquitination event supports the formation of RIPK1-RIPK3 complexes. The catalytic cysteine of A20’s deubiquitinating motif is required for inhibiting RIPK3 ubiquitination and RIPK1-RIPK3 complex formation. These studies link A20 and RIPK3 ubiquitination to necroptotic cell death, and suggest new mechanisms by which A20 may prevent inflammatory disease.
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影响因子：
32.4
作者：
Duong, Bao H.;Onizawa, Michio;Oses-Prieto, Juan A.;Advincula, Rommel;Burlingame, Alma;Malynn, Barbara A.;Ma, Averil
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