RUNDC1 inhibits autolysosome formation and survival of zebrafish via clasping ATG14-STX17-SNAP29 complex
RUNDC1 inhibits autolysosome formation and survival of zebrafish via clasping ATG14-STX17-SNAP29 complex
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DOI：
10.1038/s41418-023-01215-z
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发表时间：
2023-09-08
影响因子：
12.4
通讯作者：
Zhou，Cefan
中科院分区：
文献类型：
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作者：
Zhang，Rui;Yang，Yuyan;Zhou，Cefan
自噬是细胞或整个生物体应对营养应激的促生存机制。我们对这种融合事件的分子调控的理解仍然不完整。在这里，我们将 RUNDC1 确定为一种新型 ATG14 相互作用蛋白，该蛋白在包括斑马鱼和人类在内的脊椎动物中高度保守。通过功能获得和丧失的研究，我们证明 RUNDC1 通过抑制人类细胞和斑马鱼模型中 STX17-SNAP29-VAMP8 复合物的组装来阻断自噬体和溶酶体之间的融合，从而负向调节自噬。此外，RUNDC1 通过刺激 ATG14 同源寡聚化来扣住 ATG14-STX17-SNAP29 复合物，从而抑制 ATG14 解离。这也阻止了 VAMP8 与 STX17-SNAP29 的结合。我们进一步发现，RUNDC1 Ser379 的磷酸化对于通过促进 ATG14 同源寡聚化来抑制 STX17-SNAP29-VAMP8 复合物的组装至关重要。根据我们的研究结果，RunDC1 对于斑马鱼对营养缺乏条件的反应至关重要。综上所述，我们的研究结果表明，RUNDC1 是自噬的负调节因子，通过扣住 ATG14-STX17-SNAP29 复合物来阻碍 VAMP8 结合，从而限制自噬体与溶酶体的融合。
Autophagy serves as a pro-survival mechanism for a cell or a whole organism to cope with nutrient stress. Our understanding of the molecular regulation of this fusion event remains incomplete. Here, we identified RUNDC1 as a novel ATG14-interacting protein, which is highly conserved across vertebrates, including zebrafish and humans. By gain and loss of function studies, we demonstrate that RUNDC1 negatively modulates autophagy by blocking fusion between autophagosomes and lysosomes via inhibiting the assembly of the STX17-SNAP29-VAMP8 complex both in human cells and the zebrafish model. Moreover, RUNDC1 clasps the ATG14-STX17-SNAP29 complex via stimulating ATG14 homo-oligomerization to inhibit ATG14 dissociation. This also prevents VAMP8 from binding to STX17-SNAP29. We further identified that phosphorylation of RUNDC1 Ser379is crucial to inhibit the assembly of the STX17-SNAP29-VAMP8 complex via promoting ATG14 homo-oligomerization. In line with our findings, RunDC1 is crucial for zebrafish in their response to nutrient-deficient conditions. Taken together, our findings demonstrate that RUNDC1 is a negative regulator of autophagy that restricts autophagosome fusion with lysosomes by clasping the ATG14-STX17-SNAP29 complex to hinder VAMP8 binding.