Amphipathic N-terminal helices drive MLKL-mediated necroptosis through an antimicrobial peptide-like mechanism across evolution
文献类型：期刊论文
| 作者 | Tian, Xin1,2,3,4; Jin, Xiaotong1,2,3,4; Jiang, Shuai1,2,3,4 |
| 刊名 | DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY
 |
| 出版日期 | 2026-04-01 |
| 卷号 | 177页码:13 |
| 关键词 | Necroptosis MLKL Evolution |
| ISSN号 | 0145-305X |
| DOI | 10.1016/j.dci.2026.105574 |
| 通讯作者 | Jiang, Shuai(sjiang@qdio.ac.cn) |
| 英文摘要 | Necroptosis is a highly regulated lytic cell death executed by the pseudokinase, MLKL. Although the N-terminal 4HB domain is essential for MLKL-mediated membrane disruption, it is poorly conserved within the animal kingdom. How MLKL targets and disrupts the plasma membrane, and whether these mechanisms are evolutionarily conserved, remain incompletely understood. Using human MLKL and a teleost homolog, we found that MLKL could be activated independent of the brace region, an interdomain linker facilitating MLKL oligomerization. Instead, the N-terminal 4HB alone was sufficient to drive membrane rupture, provided that its extreme Nterminus remained intact. Stepwise removal of the N-terminal residues abolished cell death despite enhanced oligomer formation, indicating that oligomerization was a separate event and insufficient for membrane lysis. We further demonstrated that electrostatic charges and hydrophobic residues coordinated the conformational changes to enable membrane targeting, oligomerization, and permeabilization, whereas disruption of either property markedly reduced cytotoxicity. Mechanistically, the N-terminal helices displayed physicochemical features resembling antimicrobial peptides and exhibited direct membrane lysis activity in both human and fish MLKL. Despite divergence in charge distribution and amphipathic properties among species, MLKL-mediated membrane lysis was evolutionarily conserved. Consistent with this, functional residues in the N-terminal pore-forming and the C-terminal pseudokinase domains were preserved between human and teleost MLKL, with mutations in the former causing loss of function, and mutations in the latter relieving autoinhibition and triggering constitutive activation. These findings collectively reveal the molecular determinants that govern MLKLmediated cell death, highlighting how its machinery has structurally adapted while preserving its core function across evolution. |
| WOS关键词 | PROGRAMMED CELL-DEATH ; KINASE DOMAIN-LIKE ; INFLAMMATION ; EXECUTION ; APOPTOSIS ; BINDING |
| 资助项目 | National Natural Science Foundation of China[32322085] ; National Natural Science Foundation of China[42276115] ; Key Deployment Project of Centre for Ocean Mega-Research of Science, Chinese Academy of Sciences[COMS2020Q03] ; Youth Innovation Promotion Association CAS[2021204] ; Taishan Scholar Program of Shandong Province |
| WOS研究方向 | Fisheries ; Immunology ; Veterinary Sciences ; Zoology |
| 语种 | 英语 |
| WOS记录号 | WOS:001702920100001 |
| 出版者 | ELSEVIER SCI LTD |
| 源URL | [http://ir.qdio.ac.cn/handle/337002/204880]  |
| 专题 | 海洋研究所_实验海洋生物学重点实验室 |
| 通讯作者 | Jiang, Shuai |
| 作者单位 | 1.Chinese Acad Sci, Inst Oceanol, Lab Expt Marine Biol, Qingdao 266000, Peoples R China 2.Qingdao Marine Sci & Technol Ctr, Lab Marine Biol & Biotechnol, Qingdao 266000, Peoples R China 3.Chinese Acad Sci, Inst Oceanol, State Key Lab Breeding Biotechnol & Sustainable Aq, Qingdao 266000, Peoples R China 4.Univ Chinese Acad Sci, Coll Earth & Planetary Sci, Beijing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Tian, Xin,Jin, Xiaotong,Jiang, Shuai. Amphipathic N-terminal helices drive MLKL-mediated necroptosis through an antimicrobial peptide-like mechanism across evolution[J]. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY,2026,177:13. |
| APA | Tian, Xin,Jin, Xiaotong,&Jiang, Shuai.(2026).Amphipathic N-terminal helices drive MLKL-mediated necroptosis through an antimicrobial peptide-like mechanism across evolution.DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY,177,13. |
| MLA | Tian, Xin,et al."Amphipathic N-terminal helices drive MLKL-mediated necroptosis through an antimicrobial peptide-like mechanism across evolution".DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 177(2026):13. |
入库方式： OAI收割
来源：海洋研究所
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