Membrane integrity is essential for cellular survival and function. The spectrum of mechanisms protecting cellular and intracellular membranes is not fully known. Our recent work has uncovered a cellular system termed MERIT for lysosomal membrane repair, removal and replacement. Specifically, lysosomal membrane damage induces, in succession, ESCRT-dependent membrane repair, macroautophagy/autophagy-dominant removal of damaged lysosomes, and initiation of lysosomal biogenesis via transcriptional programs. The MERIT system is governed by galectins, a family of cytosolically synthesized lectins recognizing β-galactoside glycans. We found in this study that LGALS3 (galectin 3) detects membrane damage by detecting exposed lumenal glycosyl groups, recruits and organizes ESCRT components PDCD6IP/ALIX, CHMP4A, and CHMPB at damaged sites on the lysosomes, and facilitates ESCRT-driven repair of lysosomal membrane. At later stages, LGALS3 cooperates with TRIM16, an autophagy receptor-regulator, to engage autophagy machinery in removal of excessively damaged lysosomes. In the absence of LGALS3, repair and autophagy are less efficient, whereas TFEB nuclear translocation increases to compensate lysosomal deficiency via de novo lysosomal biogenesis. The MERIT system protects endomembrane integrity against a broad spectrum of agents damaging the endolysosomal network including lysosomotropic drugs, Mycobacterium tuberculosis, or neurotoxic MAPT/tau.

Abbreviations

AMPK: AMP-activated protein kinase; APEX2: engineered ascorbate peroxidase 2; ATG13: autophagy related 13; ATG16L1: autophagy related 16 like 1; BMMs: bone marrow-derived macrophages; ESCRT: endosomal sorting complexes required for transport; GPN: glycyl-L-phenylalanine 2-naphthylamide; LLOMe: L-leucyl-L-leucine methyl ester; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MERIT: membrane repair, removal and replacement; MTOR: mechanistic target of rapamycin kinase; TFEB: transcription factor EB; TFRC: transferrin receptor; TRIM16: tripartite motif-containing 16

中文翻译：

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MERIT，协调溶酶体修复，去除和置换的细胞系统。

膜完整性对于细胞存活和功能至关重要。保护细胞膜和细胞内膜的机制范围尚不完全清楚。我们最近的工作发现了一个蜂窝系统被称为MERIT溶酶体我mbrane重新PA我R，移除和replacemen ŧ。具体而言，溶酶体膜损伤连续诱导ESCRT依赖性膜修复，巨自噬/自噬显性去除受损的溶酶体，并通过转录程序引发溶酶体生物发生。MERIT系统由半乳糖凝集素控制，半乳糖凝集素是识别β-半乳糖苷聚糖的细胞质合成的凝集素家族。在这项研究中，我们发现LGALS3（半乳凝素3）通过检测暴露的腔糖基来检测膜损伤，在溶酶体的受损部位募集并组织ESCRT成分PDCD6IP / ALIX，CHMP4A和CHMPB，并促进ESCRT驱动的溶酶体膜修复。在稍后的阶段，LGALS3与自噬受体调节剂TRIM16协同作用，以使自噬机器去除过度受损的溶酶体。在没有LGALS3的情况下，修复和自噬效率较低，而TFEB核易位增加以通过从头溶酶体生物发生来补偿溶酶体缺陷。MERIT系统可保护膜的完整性，使其免受破坏溶酶体网络（包括溶溶性药物，结核分枝杆菌或神经毒性MAPT / tau。

缩略语

AMPK：AMP激活的蛋白激酶；APEX2：工程化抗坏血酸过氧化物酶2；ATG13：自噬相关的13；ATG16L1：自噬相关16像1；BMM：骨髓来源的巨噬细胞；ESCRT：运输所需的内体分选复合物；GPN：甘氨酰-L-苯丙氨酸2-萘酰胺；LLOMe：L-亮氨酰-L-亮氨酸甲酯；MAP1LC3 / LC3：微管相关蛋白1轻链3；优点：膜修复，去除和更换；MTOR：雷帕霉素激酶的机制靶标；TFEB：转录因子EB；TFRC：转铁蛋白受体；TRIM16：包含三方图案的16