Elkhalil Aladin, Whited Alec, Ghose Piya
The University of Texas at Arlington, Arlington, Texas, United States of America.
PLoS Genet. 2025 May 2;21(5):e1011696. doi: 10.1371/journal.pgen.1011696. eCollection 2025 May.
Cells may be intrinsically fated to die to sculpt tissues during development or to maintain homeostasis. Cells can also die in response to various stressors, injury or pathological conditions. Additionally, cells of the metazoan body are often highly specialized with distinct domains that differ both structurally and with respect to their neighbors. Specialized cells can also die, as in normal brain development or pathological states and their different regions may be eliminated via different programs. Clearance of different types of cell debris must be performed quickly and efficiently to prevent autoimmunity and secondary necrosis of neighboring cells. Moreover, all cells, including those programmed to die, may be subject to various stressors. Some largely unexplored questions include whether predestined cell elimination during development could be altered by stress, if adaptive stress responses exist and if polarized cells may need compartment-specific stress-adaptive programs. We leveraged Compartmentalized Cell Elimination (CCE) in the nematode C. elegans to explore these questions. CCE is a developmental cell death program whereby three segments of two embryonic polarized cell types are eliminated differently. We have previously employed this in vivo genetic system to uncover a cell compartment-specific, cell non-autonomous clearance function of the fusogen EFF-1 in phagosome closure during corpse internalization. Here, we introduce an adaptive response that serves to aid developmental phagocytosis as a part of CCE during stress. We employ a combination of forward and reverse genetics, CRISPR/Cas9 gene editing, stress response assays and advanced fluorescence microscopy. Specifically, we report that, under heat stress, the selective autophagy receptor SQST-1/p62 promotes the nuclear translocation of the oxidative stress-related transcription factor SKN-1/Nrf via negative regulation of WDR-23. This in turn allows SKN-1/Nrf to transcribe lyst-1/LYST (lysosomal trafficking associated gene) which subsequently promotes the phagocytic resolution of the developmentally-killed internalized cell even under stress conditions.
在发育过程中，细胞可能天生注定要死亡以塑造组织或维持体内平衡。细胞也可能因各种应激源、损伤或病理状况而死亡。此外，后生动物体内的细胞通常高度特化，具有不同的结构域，这些结构域在结构上以及与其相邻细胞相比都有所不同。特化细胞也可能死亡，如在正常脑发育或病理状态下，其不同区域可能通过不同程序被清除。必须快速有效地清除不同类型的细胞碎片，以防止自身免疫和邻近细胞的继发性坏死。此外，所有细胞，包括那些被编程死亡的细胞，都可能受到各种应激源的影响。一些尚未充分探索的问题包括发育过程中预定的细胞清除是否会因应激而改变、是否存在适应性应激反应以及极化细胞是否可能需要特定于细胞区室的应激适应程序。我们利用线虫秀丽隐杆线虫中的区室化细胞清除（CCE）来探索这些问题。CCE是一种发育性细胞死亡程序，通过该程序，两种胚胎极化细胞类型的三个节段以不同方式被清除。我们之前利用这个体内遗传系统揭示了融合蛋白EFF-1在尸体内化过程中吞噬体封闭方面的细胞区室特异性、细胞非自主清除功能。在这里，我们介绍一种适应性反应，作为应激期间CCE的一部分，有助于发育性吞噬作用。我们采用正向和反向遗传学、CRISPR/Cas9基因编辑、应激反应测定和先进的荧光显微镜技术相结合的方法。具体而言，我们报告称，在热应激下，选择性自噬受体SQST-1/p62通过对WDR-23的负调控促进氧化应激相关转录因子SKN-1/Nrf的核转位。这反过来又使SKN-1/Nrf能够转录lyst-1/LYST（溶酶体运输相关基因），随后即使在应激条件下也能促进发育性死亡的内化细胞的吞噬清除。
