坏死性下垂
生物
伴侣(临床)
细胞生物学
裂谷1
淀粉样蛋白(真菌学)
生物化学
程序性细胞死亡
植物
医学
细胞凋亡
病理
作者
Erpeng Wu,Wenyan He,Chenlu Wu,Zhangcheng Chen,Shijie Zhou,Xialian Wu,Yaqin Hu,Kelong Jia,Jiasong Pan,Limin Wang,Jie Qin,Dan Liu,Junxia Lu,Huayi Wang,Jixi Li,Sheng Wang,Liming Sun
出处
期刊:Cell Research
[Springer Nature]
日期:2023-08-14
卷期号:33 (11): 851-866
被引量:15
标识
DOI:10.1038/s41422-023-00859-3
摘要
Abstract Ultra-stable fibrous structure is a hallmark of amyloids. In contrast to canonical disease-related amyloids, emerging research indicates that a significant number of cellular amyloids, termed ‘functional amyloids’, contribute to signal transduction as temporal signaling hubs in humans. However, it is unclear how these functional amyloids are effectively disassembled to terminate signal transduction. RHIM motif-containing amyloids, the largest functional amyloid family discovered thus far, play an important role in mediating necroptosis signal transduction in mammalian cells. Here, we identify heat shock protein family A member 8 (HSPA8) as a new type of enzyme — which we name as ‘amyloidase’ — that directly disassembles RHIM-amyloids to inhibit necroptosis signaling in cells and mice. Different from its role in chaperone-mediated autophagy where it selects substrates containing a KFERQ-like motif, HSPA8 specifically recognizes RHIM-containing proteins through a hydrophobic hexapeptide motif N(X 1 )φ(X 3 ). The SBD domain of HSPA8 interacts with RHIM-containing proteins, preventing proximate RHIM monomers from stacking into functional fibrils; furthermore, with the NBD domain supplying energy via ATP hydrolysis, HSPA8 breaks down pre-formed RHIM-amyloids into non-functional monomers. Notably, HSPA8’s amyloidase activity in disassembling functional RHIM-amyloids does not require its co-chaperone system. Using this amyloidase activity, HSPA8 reverses the initiator RHIM-amyloids (formed by RIP1, ZBP1, and TRIF) to prevent necroptosis initiation, and reverses RIP3-amyloid to prevent necroptosis execution, thus eliminating multi-level RHIM-amyloids to effectively prevent spontaneous necroptosis activation. The discovery that HSPA8 acts as an amyloidase dismantling functional amyloids provides a fundamental understanding of the reversibility nature of functional amyloids, a property distinguishing them from disease-related amyloids that are unbreakable in vivo.
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