WIPI2在经典自噬和非经典自噬中的作用

Emerging roles of WIPI2 in canonical and non-canonical autophagy

细胞自噬是真核生物特有的依赖溶酶体的细胞内降解途径,通过清除蛋白聚集体、受损细胞器和入侵病原体等细胞内容物,维持细胞内环境稳定.WIPI蛋白是在哺乳动物细胞中鉴定的与细胞自噬密切相关的一类蛋白家族.其中,WIPI2主要调控自噬前体的延伸过程,是直接参与自噬小体形成的少数必需蛋白之一.WIPI2可通过多种不同的作用方式行使功能.近年来的研究发现,除了营养剥夺诱导的经典自噬,WIPI2对于病毒感染诱导的非经典自噬同样必不可少.而且,在不同类型的自噬途径中,不同的细胞内外刺激信号可通过调控WIPI2的蛋白稳定性或者WIPI2与自噬前体的亲和力,影响细胞内的自噬水平,帮助细胞更好地应对内外环境的改变.值得一提的是,WIPI2的功能缺失突变与一类引起发育障碍的人类遗传病相关.本文主要围绕WIPI2在经典自噬和非经典自噬中的作用方式与调控机制,综述近年来的研究进展.

Macroautophagy(hereafter referred to as autophagy)is a highly conserved lysosome-dependent degradation pathway in eukaryotic cells.Autophagy helps maintain cell homeostasis by eliminating unwanted cellular materials,including protein aggregates,damaged organelles and invading pathogens.Dysfunction of autophagy has been linked to a variety of human diseases,such as cancers,metabolic diseases and neurodegenerative diseases.As a sequential cellular process,autophagy is typically divided into several major steps,including autophagy initiation,membrane nucleation,phagophore expansion,autophagosome formation and autophagosome-lysosome fusion.These distinct autophagy steps are spatiotemporally controlled by a great number of autophagy-related proteins.Among these proteins,WIPI-family proteins,comprised with four members,have been demonstrated to play an important role in phagophore expansion.Mammalian WIPI1 and WIPI2 are highly related to yeast Atg18 while mammalian WIPI3 and WIPI4 are highly close to yeast Atg21.Of note,WIPI2 but not WIPI1 is essential for autophagy,and WIPI3 and WIPI4 are each only partially necessary for autophagy.During canonical autophagy,WIPI2 has been demonstrated to regulate phagophore expansion through several different mechanisms.On the phagophore,PI3P,produced by activated VPS34 complex,and RAB11A mediate the recruitment of WIPI2,which then recruits ATG16L1-ATG5-ATG12 complex by interacting with ATG16L1,resulting in the lipidation of ATG8-family proteins and the expansion of phagophore.Recently,WIPI2 is also shown to promote phagophore expansion by mediating the membrane contact between phagophore and endoplasmic reticulum through interacting with endoplasmic reticulum-localized ULK1 complex.In addition to nutrient starvation-induced canonical autophagy,WIPI2 is required for viral infection-induced non-canonical autophagy,which depends on the activation of cGAS-STING pathway.Interestingly,STING-induced autophagy does not require the upstream autophagic machinery,such as ULK1 complex and VPS34 complex.Stimulated by cytoplasmic DNA,activated cGAS synthesizes cGAMP,which binds to endoplasmic reticulumlocalized STING to initiate its intracellular trafficking,leading to STING vesicle formation.By providing membrane sources,STING vesicles act as the primary sites for autophagosome formation.Through a direct interaction,STING brings WIPI2 to STING vesicles to mediate the subsequent recruitment of ATG16L1-ATG5-ATG12 complex,bypassing the upstream autophagic machinery.In response to different cellular or extracellular cues,a variety of WIPI2-based regulation mechanisms are adopted by the cell to tightly control autophagy.Under nutrient-rich conditions,activated mTORC1 phosphorylates WIPI2 to enhance its binding to E3 ubiquitin ligase HUWE1,leading to the proteasomal degradation of WIPI2 and the suppression of autophagy.Upon mitosis induction,activated E3 ubiquitin ligase CRL4 interacts with WIPI2 to promote its ubiquitination and proteasome-dependent degradation,resulting in autophagy inhibition.During bacterial infection,activated TBK1 promotes the recruitment of WIPI2-localized phagophores to bacteria for the initiation of xenophagy and the clearance of bacteria.It is worth noting that a mutation of WIPI2,decreasing its autophagic function,is associated with global developmental abnormalities in humans.In this paper,we aim to review the emerging roles of WIPI2 in the regulation of canonical and non-canonical autophagy.