ROCK1 但不是 LIMK1 或 PAK2 是凋亡膜起泡和细胞分解的关键调节因子,Cell Death and Differentiation

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ROCK1 但不是 LIMK1 或 PAK2 是凋亡膜起泡和细胞分解的关键调节因子
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2019-05-01 , DOI: 10.1038/s41418-019-0342-5
Rochelle Tixeira , Thanh Kha Phan , Sarah Caruso , Bo Shi , Georgia K. Atkin-Smith , Christina Nedeva , Jenny D. Y. Chow , Hamsa Puthalakath , Mark D. Hulett , Marco J. Herold , Ivan K. H. Poon

已知许多细胞类型在细胞凋亡过程中经历一系列形态变化，导致它们分解成较小的膜结合囊泡，称为凋亡小体 (ApoBD)。特别是，在凋亡细胞表面形成称为膜泡的圆形凸起是许多细胞类型生成 ApoBD 所需的关键形态学步骤。虽然细胞凋亡膜起泡被认为受包括 ROCK1、PAK2 和 LIMK1 在内的激酶调节，但尚不清楚这些激酶是否在凋亡细胞的分解中表现出重叠的作用。利用基于药理学和 CRISPR/Cas9 基因编辑的方法，我们将 ROCK1 但不是 PAK2 或 LIMK1 确定为凋亡膜起泡和 ApoBD 形成的关键非冗余正调节因子。在功能上，我们已经建立了一个实验系统来抑制或增强 ApoBD 的形成，并证明了凋亡细胞分解在各种吞噬细胞有效吸收凋亡材料中的重要性。出乎意料的是，我们还注意到 ROCK1 可以在调节继发性坏死的发生中发挥作用。总之，这些数据揭示了细胞凋亡过程中细胞分解的机制和功能。

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ROCK1 but not LIMK1 or PAK2 is a key regulator of apoptotic membrane blebbing and cell disassembly

Many cell types are known to undergo a series of morphological changes during the progression of apoptosis, leading to their disassembly into smaller membrane-bound vesicles known as apoptotic bodies (ApoBDs). In particular, the formation of circular bulges called membrane blebs on the surface of apoptotic cells is a key morphological step required for a number of cell types to generate ApoBDs. Although apoptotic membrane blebbing is thought to be regulated by kinases including ROCK1, PAK2 and LIMK1, it is unclear whether these kinases exhibit overlapping roles in the disassembly of apoptotic cells. Utilising both pharmacological and CRISPR/Cas9 gene editing based approaches, we identified ROCK1 but not PAK2 or LIMK1 as a key non-redundant positive regulator of apoptotic membrane blebbing as well as ApoBD formation. Functionally, we have established an experimental system to either inhibit or enhance ApoBD formation and demonstrated the importance of apoptotic cell disassembly in the efficient uptake of apoptotic materials by various phagocytes. Unexpectedly, we also noted that ROCK1 could play a role in regulating the onset of secondary necrosis. Together, these data shed light on both the mechanism and function of cell disassembly during apoptosis.

更新日期：2019-05-01

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