Regulation of ATG4B stability by RNF5 limits basal levels of autophagy and influences susceptibility to bacterial infection.
Regulation of ATG4B stability by RNF5 limits basal levels of autophagy and influences susceptibility to bacterial infection.
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RNF5对ATG4B稳定性的调节限制了自噬的基础水平，并影响细菌感染的易感性。
DOI：
10.1371/journal.pgen.1003007
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Ronai ZA
中科院分区：
文献类型：
--
作者：
Kuang E;Okumura CY;Sheffy-Levin S;Varsano T;Shu VC;Qi J;Niesman IR;Yang HJ;López-Otín C;Yang WY;Reed JC;Broday L;Nizet V;Ronai ZA
自噬是一种细胞质成分和细胞器被溶酶体机制降解的机制，以响应包括营养剥夺、细胞内病原体和多种形式的细胞应激在内的各种刺激。在这里，我们表明，膜相关的E3连接酶RNF5通过控制选择的半胱氨酸蛋白酶ATG4B池的稳定性来调节自噬的基础水平。RNF5控制ATG4B的膜部分并限制LC3(ATG8)的加工，这是吞噬体和自噬小体形成所必需的。ATG4B与-RNF5泛素化和稳定性的关联以及-RNF5对其泛素化和稳定性的调节主要在正常生长条件下看到。RNF5MEF的Lc3型加工、Lc3阳性斑点的出现和p62的表达均高于−/−。RNF5突变体保留了其E3连接酶活性，但不与ATG4B相关，不再影响Lc3点。此外，使用WT而不是Lc3突变体的RNF5−/−中的斑点增加，从而绕过了ATG4B处理，证实了RNF5在Lc3处理和自噬的早期阶段所起的作用。同样，秀丽线虫中RNF-5的失活会增加LGG-1/LC3：：GFP斑点的水平。RNF5−/−小鼠对A组链球菌感染的抵抗力更强，与自噬小体增加和RNF5−/−巨噬细胞更有效地清除细菌有关。总的来说，RNF5介导的膜ATG4B控制揭示了一个新的层，在LC 3加工和自噬的调节中。自噬是细胞内的分解代谢过程，细胞自身的成分通过溶酶体机制降解。自噬与多种细胞过程有关，如生长发育、癌症和炎症。利用生物化学、细胞生物学和遗传模型，我们确定了一种泛素连接酶，它可以在没有诱导性刺激(如饥饿)的情况下限制自噬。基础自噬的控制是由泛素连接酶RNF5通过其对膜相关ATG4B蛋白酶的调节而介导的。使用RNF5突变小鼠，我们证明了这种调节对于限制细菌病原体在细胞内感染的宿主防御机制的意义。
Autophagy is the mechanism by which cytoplasmic components and organelles are degraded by the lysosomal machinery in response to diverse stimuli including nutrient deprivation, intracellular pathogens, and multiple forms of cellular stress. Here, we show that the membrane-associated E3 ligase RNF5 regulates basal levels of autophagy by controlling the stability of a select pool of the cysteine protease ATG4B. RNF5 controls the membranal fraction of ATG4B and limits LC3 (ATG8) processing, which is required for phagophore and autophagosome formation. The association of ATG4B with—and regulation of its ubiquitination and stability by—RNF5 is seen primarily under normal growth conditions. Processing of LC3 forms, appearance of LC3-positive puncta, and p62 expression are higher in RNF5−/− MEF. RNF5 mutant, which retains its E3 ligase activity but does not associate with ATG4B, no longer affects LC3 puncta. Further, increased puncta seen in RNF5−/− using WT but not LC3 mutant, which bypasses ATG4B processing, substantiates the role of RNF5 in early phases of LC3 processing and autophagy. Similarly, RNF-5 inactivation in Caenorhabditis elegans increases the level of LGG-1/LC3::GFP puncta. RNF5−/− mice are more resistant to group A Streptococcus infection, associated with increased autophagosomes and more efficient bacterial clearance by RNF5−/− macrophages. Collectively, the RNF5-mediated control of membranalATG4B reveals a novel layer in the regulation of LC3 processing and autophagy. Autophagy is an intracellular catabolic process by which a cell's own components are degraded through the lysosomal machinery. Autophagy is implicated in various cellular processes such as growth and development, cancer, and inflammation. Using biochemistry, cell biology, and genetic models, we identify a ubiquitin ligase that limits autophagy in the absence of an inducing stimulus (e.g. starvation). The control of basal autophagy is mediated by the ubiquitin ligase RNF5 through its regulation of the membrane-associated ATG4B protease. Using RNF5 mutant mice we demonstrate the implications of this regulation for host defense mechanisms that limit intracellular infection by bacterial pathogens.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
16
作者：
Ganley IG;Wong PM;Gammoh N;Jiang X
通讯作者：
Jiang X
影响因子：
64.8
作者：
Ichimura, Y;Kirisako, T;Ohsumi, Y
通讯作者：
Ohsumi, Y
影响因子：
3.3
作者：
De Vries, L;Elenko, E;Farquhar, MG
通讯作者：
Farquhar, MG
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D