Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance.
Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance.
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DOI：
10.1038/s41467-021-23474-5
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发表时间：
2021-06-07
影响因子：
16.6
通讯作者：
Meier P
中科院分区：
文献类型：
--
作者：
Garcia LR;Tenev T;Newman R;Haich RO;Liccardi G;John SW;Annibaldi A;Yu L;Pardo M;Young SN;Fitzgibbon C;Fernando W;Guppy N;Kim H;Liang LY;Lucet IS;Kueh A;Roxanis I;Gazinska P;Sims M;Smyth T;Ward G;Bertin J;Beal AM;Geddes B;Choudhary JS;Murphy JM;Aurelia Ball K;Upton JW;Meier P
坏死性上睑下垂是一种溶解性、炎症性的细胞死亡形式，它不仅有助于病原体的清除，而且还可能导致疾病的发病机制。坏死下垂是由ripk3介导的MLKL磷酸化引发的，该磷酸化被认为会引发MLKL寡聚化、膜易位和膜破裂，尽管其确切机制尚不完全清楚。在这里，我们发现k63连接的泛素链在坏死坏死过程中附着在MLKL上，并且K219位点的MLKL泛素化显著地促进了磷酸化MLKL的细胞毒性潜能。K219R MLKL突变保护动物免受坏死性坏死诱导的皮肤损伤，并使细胞抵抗病原体诱导的坏死性坏死。从机制上讲，我们发现K219位点的MLKL泛素化是MLKL在膜上的高阶组装所必需的，从而促进其破裂和坏死。我们证明K219泛素化允许MLKL活性诱导溶解性细胞死亡，这表明病原体的坏死清除以及MLKL依赖性病理受到泛素信号系统的影响。坏死坏死是一种细胞死亡形式，其特征是通过MLKL寡聚化导致膜破裂，尽管机制细节尚不清楚。在这里，作者表明，K219的MLKL泛素化促进了高阶膜组装和随后的破裂，促进了细胞毒性。
Necroptosis is a lytic, inflammatory form of cell death that not only contributes to pathogen clearance but can also lead to disease pathogenesis. Necroptosis is triggered by RIPK3-mediated phosphorylation of MLKL, which is thought to initiate MLKL oligomerisation, membrane translocation and membrane rupture, although the precise mechanism is incompletely understood. Here, we show that K63-linked ubiquitin chains are attached to MLKL during necroptosis and that ubiquitylation of MLKL at K219 significantly contributes to the cytotoxic potential of phosphorylated MLKL. The K219R MLKL mutation protects animals from necroptosis-induced skin damage and renders cells resistant to pathogen-induced necroptosis. Mechanistically, we show that ubiquitylation of MLKL at K219 is required for higher-order assembly of MLKL at membranes, facilitating its rupture and necroptosis. We demonstrate that K219 ubiquitylation licenses MLKL activity to induce lytic cell death, suggesting that necroptotic clearance of pathogens as well as MLKL-dependent pathologies are influenced by the ubiquitin-signalling system. Necroptosis is a form of cell death characterized by membrane rupture via MLKL oligomerization, although mechanistic details remain unclear. Here, the authors show that MLKL ubiquitylation of K219 facilitates high-order membrane assembly and subsequent rupture, promoting cytotoxicity.
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影响因子：
16
作者：
Choi, Seung-Won;Park, Han-Hee;Kim, You-Sun
通讯作者：
Kim, You-Sun
影响因子：
12.4
作者：
Davies, Katherine A.;Tanzer, Maria C.;Murphy, James M.
通讯作者：
Murphy, James M.
影响因子：
4.8
作者：
Lewis, J;Devin, A;Liu, ZG
通讯作者：
Liu, ZG
DOI：
10.1007/978-1-4939-8754-2_8
发表时间：
2018-01-01
期刊：
PROGRAMMED NECROSIS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Cai, Zhenyu;Liu, Zheng-Gang
通讯作者：
Liu, Zheng-Gang
影响因子：
16.8
作者：
Akimov, Vyacheslav;Barrio-Hernandez, Inigo;Blagoev, Blagoy
通讯作者：
Blagoev, Blagoy