BORC coordinates encounter and fusion of lysosomes with autophagosomes.
BORC coordinates encounter and fusion of lysosomes with autophagosomes.
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DOI：
10.1080/15548627.2017.1343768
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发表时间：
2017-10-03
期刊：
影响因子：
13.3
通讯作者：
Bonifacino JS
中科院分区：
文献类型：
--
作者：
Jia R;Guardia CM;Pu J;Chen Y;Bonifacino JS
在过去的二十年里，自噬小体形成的机制已经被广泛研究，而那些负责自噬小体-溶酶体融合的机制直到最近才开始引起人们的注意。在这项研究中，我们报告了多亚单位BORC复合体是有效的自噬小体-溶酶体融合所必需的，该复合体先前参与了溶酶体动蛋白依赖性的向细胞外围移动。BORC亚基的敲除(KO)不仅导致溶酶体的核旁聚集，而且还导致自噬蛋白LC3B-II和受体SQSTM1水平的增加。在不改变基础mTORC1活性和自噬启动的情况下，LC3B-II的表达增加。相反，LC3B-II的积累主要是由于溶酶体降解减少所致。进一步的实验表明，BORC KO既损害了自噬小体与溶酶体的相遇，也削弱了其与溶酶体的融合。减少接触的原因是溶酶体不能向形成许多自噬小体的外周细胞质移动。然而，BORC KO也减少了啤酒花拴系复合体向溶酶体的招募，以及参与自噬小体-溶酶体融合的STX17-VAMP8-SNAP29反式SNAPE复合体的组装。通过这些双重作用，BORC将依赖于激动素的溶酶体向自噬小体的运动与依赖于啤酒花的自噬小体-溶酶体融合结合在一起。这些发现揭示了自噬中溶酶体分散的要求，这与mTORC1信号的变化无关，并确认BORC是自噬小体-溶酶体融合的新调节因子。
Whereas the mechanisms involved in autophagosome formation have been extensively studied for the past 2 decades, those responsible for autophagosome-lysosome fusion have only recently begun to garner attention. In this study, we report that the multisubunit BORC complex, previously implicated in kinesin-dependent movement of lysosomes toward the cell periphery, is required for efficient autophagosome-lysosome fusion. Knockout (KO) of BORC subunits causes not only juxtanuclear clustering of lysosomes, but also increased levels of the autophagy protein LC3B-II and the receptor SQSTM1. Increases in LC3B-II occur without changes in basal MTORC1 activity and autophagy initiation. Instead, LC3B-II accumulation largely results from decreased lysosomal degradation. Further experiments show that BORC KO impairs both the encounter and fusion of autophagosomes with lysosomes. Reduced encounters result from an inability of lysosomes to move toward the peripheral cytoplasm, where many autophagosomes are formed. However, BORC KO also reduces the recruitment of the HOPS tethering complex to lysosomes and assembly of the STX17-VAMP8-SNAP29 trans-SNARE complex involved in autophagosome-lysosome fusion. Through these dual roles, BORC integrates the kinesin-dependent movement of lysosomes toward autophagosomes with HOPS-dependent autophagosome-lysosome fusion. These findings reveal a requirement for lysosome dispersal in autophagy that is independent of changes in MTORC1 signaling, and identify BORC as a novel regulator of autophagosome-lysosome fusion.
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
32.4
作者：
Garg S;Sharma M;Ung C;Tuli A;Barral DC;Hava DL;Veerapen N;Besra GS;Hacohen N;Brenner MB
通讯作者：
Brenner MB
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
11.8
作者：
Fu, Meng-meng;Nirschl, Jeffrey J.;Holzbaur, Erika L. F.
通讯作者：
Holzbaur, Erika L. F.
影响因子：
1.5
作者：
Kimura, Shunsuke;Noda, Takeshi;Yoshimori, Tamotsu
通讯作者：
Yoshimori, Tamotsu