中国科学院分子细胞卓越创新中心孙丽明小组在研究中取得进展。他们的研究发现HSPA8作为淀粉样蛋白酶通过抑制和逆转功能性淀粉样蛋白的形成抑制坏死性凋亡。相关论文于2023年8月14日发表于国际学术期刊《细胞研究》杂志。

研究人员发现热休克蛋白家族A成员8（HSPA8）是一种新型酶（并将其命名为“淀粉样蛋白酶”）直接分解RHIM-淀粉样蛋白以抑制细胞和小鼠坏死性凋亡信号传导。与其在自噬中作为伴侣蛋白的功能不同，HSPA8靶向含有KFERQ样基序的底物，HSPA8通过疏水性六肽基序N（X₁）φ（X₃）特异性识别含RHIM的蛋白质。HSPA8的SBD结构域与含RIM结构域的蛋白质相互作用，防止RIM单体堆积成功能性原纤维。

此外，随着NBD结构域通过水解ATP提供能量，HSPA8将预先形成的RHIM-淀粉样蛋白分解成非功能性单体。值得注意的是，HSPA8在发挥淀粉样蛋白酶活性分解功能性RHIM-淀粉样蛋白时并不需要其共伴侣的存在。利用这种淀粉样蛋白酶活性，HSPA8逆转RHIM-淀粉样蛋白的形成（由RIP1、ZBP1和TRIF形成）以阻止坏死性凋亡的开始，并降解RIP3-淀粉样蛋白以防止坏死性凋亡的执行，从而消除多级RHIM-淀粉样蛋白，有效防止自发性坏死性凋亡的激活。HSPA8作为淀粉样蛋白酶分解功能性淀粉样蛋白的发现提供了对功能性淀粉样蛋白可逆性的基本理解，这是将它们与体内已知与疾病相关淀粉样蛋白区分开来的标志。

据了解，淀粉样蛋白具有超稳定的纤维结构。与疾病相关典型的淀粉样蛋白相比，最近的研究表明，许多细胞淀粉样蛋白（称为“功能性淀粉样蛋白”）可作为时间信号中枢参与信号转导。然而，目前尚不清楚这些功能淀粉样蛋白如何有效地降解以终止信号转导。含RIM基序的淀粉样蛋白是迄今为止发现的最大的功能性淀粉样蛋白家族，在哺乳动物细胞坏死性凋亡信号转导中起重要作用。

附：英文原文

Title: HSPA8 acts as an amyloidase to suppress necroptosis by inhibiting and reversing functional amyloid formation

Author: Wu, Erpeng, He, Wenyan, Wu, Chenlu, Chen, Zhangcheng, Zhou, Shijie, Wu, Xialian, Hu, Zhiheng, Jia, Kelong, Pan, Jiasong, Wang, Limin, Qin, Jie, Liu, Dan, Lu, Junxia, Wang, Huayi, Li, Jixi, Wang, Sheng, Sun, Liming

Issue&Volume: 2023-08-14

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(X1)φ(X3). 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.

DOI: 10.1038/s41422-023-00859-3

Source: https://www.nature.com/articles/s41422-023-00859-3