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磷酸肌醇信号通路介导快速溶酶体修复
Nature
(
IF
50.5
)
Pub Date : 2022-09-07
, DOI:
10.1038/s41586-022-05164-4
Jay Xiaojun Tan
1,
2
,
Toren Finkel
1,
3
Affiliation
- Aging Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
溶酶体功能障碍与疾病和正常衰老的关系日益密切1,2 。溶酶体膜透化 (LMP) 是溶酶体相关疾病的标志,可由多种细胞应激源触发3 。鉴于溶酶体的破坏性内容,LMP 必须迅速解决,尽管其潜在机制尚不清楚。在这里,我们使用无偏见的蛋白质组学方法,表明 LMP 刺激磷酸肌醇引发的膜束缚和脂质转运 (PITT) 途径,以实现快速溶酶体修复。末次月经后,磷脂酰肌醇 4 激酶 2α (PI4K2A) 在受损的溶酶体上快速积累,产生高水平的脂质信使磷脂酰肌醇 4-磷酸。溶酶体 4-磷酸磷脂酰肌醇反过来招募多个氧甾醇结合蛋白 (OSBP) 相关蛋白 (ORP) 家族成员,包括 ORP9、ORP10、ORP11 和 OSBP,以在受损的溶酶体和内质网之间协调广泛的新膜接触位点。 ORP 随后催化磷脂酰丝氨酸和胆固醇的强大内质网到溶酶体的转移,以支持快速溶酶体修复。最后,脂质转移蛋白 ATG2 也被招募到受损的溶酶体中,其活性受到磷脂酰丝氨酸的强力刺激。 ATG2 独立于巨自噬,通过直接溶酶体脂质转移介导快速膜修复。总之,我们的研究结果表明,PITT 途径维持溶酶体膜的完整性,对许多以溶酶体功能受损为特征的与年龄相关的疾病具有重要意义。
"点击查看英文标题和摘要"
A phosphoinositide signalling pathway mediates rapid lysosomal repair
Lysosomal dysfunction has been increasingly linked to disease and normal ageing1,2. Lysosomal membrane permeabilization (LMP), a hallmark of lysosome-related diseases, can be triggered by diverse cellular stressors3. Given the damaging contents of lysosomes, LMP must be rapidly resolved, although the underlying mechanisms are poorly understood. Here, using an unbiased proteomic approach, we show that LMP stimulates a phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair. Upon LMP, phosphatidylinositol-4 kinase type 2α (PI4K2A) accumulates rapidly on damaged lysosomes, generating high levels of the lipid messenger phosphatidylinositol-4-phosphate. Lysosomal phosphatidylinositol-4-phosphate in turn recruits multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members, including ORP9, ORP10, ORP11 and OSBP, to orchestrate extensive new membrane contact sites between damaged lysosomes and the endoplasmic reticulum. The ORPs subsequently catalyse robust endoplasmic reticulum-to-lysosome transfer of phosphatidylserine and cholesterol to support rapid lysosomal repair. Finally, the lipid transfer protein ATG2 is also recruited to damaged lysosomes where its activity is potently stimulated by phosphatidylserine. Independent of macroautophagy, ATG2 mediates rapid membrane repair through direct lysosomal lipid transfer. Together, our findings identify that the PITT pathway maintains lysosomal membrane integrity, with important implications for numerous age-related diseases characterized by impaired lysosomal function.
更新日期:2022-09-08