The ATG5-binding and coiled coil domains of ATG16L1 maintain autophagy and tissue homeostasis in mice independently of the WD domain required for LC3-associated phagocytosis.
The ATG5-binding and coiled coil domains of ATG16L1 maintain autophagy and tissue homeostasis in mice independently of the WD domain required for LC3-associated phagocytosis.
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DOI：
10.1080/15548627.2018.1534507
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发表时间：
2019-04
期刊：
影响因子：
13.3
通讯作者：
Wileman T
中科院分区：
文献类型：
--
作者：
Rai S;Arasteh M;Jefferson M;Pearson T;Wang Y;Zhang W;Bicsak B;Divekar D;Powell PP;Naumann R;Beraza N;Carding SR;Florey O;Mayer U;Wileman T
巨噬/自噬将受损的蛋白和细胞器传递给溶酶体降解，在通过减少组织损伤来维持组织稳态方面发挥重要作用。在自噬过程中，LC3易位到吞噬体（自噬体的前体）的限制膜上，为自噬物质提供了一个结合位点，并促进了与溶酶体的融合。一种称为LC3相关吞噬（LAP）的自噬相关途径在细菌和真菌病原体的摄取过程中将LC3靶向到吞噬体和核内体膜，并将LC3靶向到含有颗粒物质或凋亡细胞的肿胀核内体。我们通过观察ATG16L1的WD结构域是LAP所必需的，而不是自噬所必需的，研究了自噬和LAP在体内的作用。缺乏连接体和WD结构域的小鼠可以激活自噬，但缺乏LAP。LAP - /-小鼠在出生后的饥饿中存活，生长速度与对照组相同，并且具有生育能力。这些小鼠的肝脏、肾脏、大脑和肌肉维持了与对照组相似的LC3和SQSTM1/p62等自噬物质的水平，并防止了SQSTM1内含物的积累和与自噬丧失相关的组织损伤。结果表明，小鼠自噬维持组织稳态独立于lc3相关吞噬。WIPI2结合所需的螺旋结构域谷氨酸E230的进一步缺失会导致自噬缺陷小鼠在新生儿饥饿中存活。对脑裂解物的分析表明，WIPI2和ATG16L1之间的相互作用对脑自噬不太重要，这可能允许低水平的自噬克服新生儿死亡率。缩写:CCD:线圈域;CYBB/NOX2：细胞色素b-245: β多肽；GPT/ALT：谷丙转氨酶：可溶性；LAP: lc3相关吞噬；LC3：微管相关蛋白1轻链3；MEF：小鼠胚胎成纤维细胞；NOD：核苷酸结合寡聚结构域；NADPH：烟酰胺腺嘌呤二核苷酸磷酸；RUBCN/Rubicon：含有Beclin 1相互作用蛋白的RUN结构域和富含半胱氨酸的结构域；SLE：系统性红斑狼疮；SQSTM1/p62: sequestosome 1；TLR: toll样受体；TMEM：跨膜蛋白；TRIM：三方基序蛋白；UVRAG：抗紫外线相关基因；WD：色氨酸-天冬氨酸；WIPI: WD 40重复结构域：磷酸肌苷相互作用
Macroautophagy/autophagy delivers damaged proteins and organelles to lysosomes for degradation, and plays important roles in maintaining tissue homeostasis by reducing tissue damage. The translocation of LC3 to the limiting membrane of the phagophore, the precursor to the autophagosome, during autophagy provides a binding site for autophagy cargoes, and facilitates fusion with lysosomes. An autophagy-related pathway called LC3-associated phagocytosis (LAP) targets LC3 to phagosome and endosome membranes during uptake of bacterial and fungal pathogens, and targets LC3 to swollen endosomes containing particulate material or apoptotic cells. We have investigated the roles played by autophagy and LAP in vivo by exploiting the observation that the WD domain of ATG16L1 is required for LAP, but not autophagy. Mice lacking the linker and WD domains, activate autophagy, but are deficient in LAP. The LAP−/- mice survive postnatal starvation, grow at the same rate as littermate controls, and are fertile. The liver, kidney, brain and muscle of these mice maintain levels of autophagy cargoes such as LC3 and SQSTM1/p62 similar to littermate controls, and prevent accumulation of SQSTM1 inclusions and tissue damage associated with loss of autophagy. The results suggest that autophagy maintains tissue homeostasis in mice independently of LC3-associated phagocytosis. Further deletion of glutamate E230 in the coiled-coil domain required for WIPI2 binding produced mice with defective autophagy that survived neonatal starvation. Analysis of brain lysates suggested that interactions between WIPI2 and ATG16L1 were less critical for autophagy in the brain, which may allow a low level of autophagy to overcome neonatal lethality. Abbreviations: CCD: coiled-coil domain; CYBB/NOX2: cytochrome b-245: beta polypeptide; GPT/ALT: glutamic pyruvic transaminase: soluble; LAP: LC3-associated phagocytosis; LC3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; NOD: nucleotide-binding oligomerization domain; NADPH: nicotinamide adenine dinucleotide phosphate; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing Beclin 1-interacting protein; SLE: systemic lupus erythematosus; SQSTM1/p62: sequestosome 1; TLR: toll-like receptor; TMEM: transmembrane protein; TRIM: tripartite motif-containing protein; UVRAG: UV radiation resistance associated gene; WD: tryptophan-aspartic acid; WIPI: WD 40 repeat domain: phosphoinositide interacting
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影响因子：
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作者：
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DOI：
10.1083/jcb.201503023
发表时间：
2015-09-14
期刊：
The Journal of cell biology
影响因子：
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