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The ER-Localized Transmembrane Protein TMEM39A/SUSR2 Regulates Autophagy by Controlling the Trafficking of the PtdIns(4)P Phosphatase SAC1.
Molecular Cell ( IF 14.5 ) Pub Date : 2019-12-02 , DOI: 10.1016/j.molcel.2019.10.035 Guangyan Miao 1 , Yujie Zhang 1 , Di Chen 1 , Hong Zhang 2
Molecular Cell ( IF 14.5 ) Pub Date : 2019-12-02 , DOI: 10.1016/j.molcel.2019.10.035 Guangyan Miao 1 , Yujie Zhang 1 , Di Chen 1 , Hong Zhang 2
Affiliation
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TMEM39A, encoding an ER-localized transmembrane protein, is a susceptibility locus for multiple autoimmune diseases. The molecular function of TMEM39A remains completely unknown. Here we demonstrated that TMEM39A, also called SUSR2, modulates autophagy activity by regulating the spatial distribution and levels of PtdIns(4)P. Depletion of SUSR2 elevates late endosomal/lysosomal PtdIns(4)P levels, facilitating recruitment of the HOPS complex to promote assembly of the SNARE complex for autophagosome maturation. SUSR2 knockdown also increases the degradative capability of lysosomes. Mechanistically, SUSR2 interacts with the ER-localized PtdIns(4)P phosphatase SAC1 and also the COPII SEC23/SEC24 subunits to promote the ER-to-Golgi transport of SAC1. Retention of SAC1 on the ER in SUSR2 knockdown cells increases the level of PtdIns(3)P produced by the VPS34 complex, promoting autophagosome formation. Our study reveals that TMEM39A/SUSR2 acts as an adaptor protein for efficient export of SAC1 from the ER and provides insights into the pathogenesis of diseases associated with TMEM39A mutations.
中文翻译：
ER本地化跨膜蛋白TMEM39A / SUSR2通过控制PtdIns（4）P磷酸酶SAC1的贩运来调节自噬。
编码ER定位跨膜蛋白的TMEM39A是多种自身免疫性疾病的易感性基因位点。TMEM39A的分子功能仍然完全未知。在这里，我们证明了TMEM39A，也称为SUSR2，通过调节PtdIns（4）P的空间分布和水平来调节自噬活性。SUSR2的耗竭提高了晚期内体/溶酶体PtdIns（4）P的水平，促进了HOPS复合物的募集，以促进SNARE复合物的组装以实现自噬体的成熟。SUSR2敲低还增加了溶酶体的降解能力。从机制上讲，SUSR2与ER定位的PtdIns（4）P磷酸酶SAC1以及COPII SEC23 / SEC24亚基相互作用，以促进SAC1的ER到高尔基体运输。SASR1敲低细胞中ER上SAC1的保留增加了VPS34复合物产生的PtdIns（3）P的水平，促进了自噬体的形成。我们的研究表明，TMEM39A / SUSR2充当衔接子蛋白，可从ER有效输出SAC1，并为与TMEM39A突变相关的疾病的发病机理提供了见识。
更新日期：2019-12-02
中文翻译：
ER本地化跨膜蛋白TMEM39A / SUSR2通过控制PtdIns（4）P磷酸酶SAC1的贩运来调节自噬。
编码ER定位跨膜蛋白的TMEM39A是多种自身免疫性疾病的易感性基因位点。TMEM39A的分子功能仍然完全未知。在这里，我们证明了TMEM39A，也称为SUSR2，通过调节PtdIns（4）P的空间分布和水平来调节自噬活性。SUSR2的耗竭提高了晚期内体/溶酶体PtdIns（4）P的水平，促进了HOPS复合物的募集，以促进SNARE复合物的组装以实现自噬体的成熟。SUSR2敲低还增加了溶酶体的降解能力。从机制上讲，SUSR2与ER定位的PtdIns（4）P磷酸酶SAC1以及COPII SEC23 / SEC24亚基相互作用，以促进SAC1的ER到高尔基体运输。SASR1敲低细胞中ER上SAC1的保留增加了VPS34复合物产生的PtdIns（3）P的水平，促进了自噬体的形成。我们的研究表明，TMEM39A / SUSR2充当衔接子蛋白，可从ER有效输出SAC1，并为与TMEM39A突变相关的疾病的发病机理提供了见识。
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