Mdm1/Snx13 is a novel ER-endolysosomal interorganelle tethering protein.
Mdm1/Snx13 is a novel ER-endolysosomal interorganelle tethering protein.
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MDM1/SNX13是一种新型的ER-内糖体间束缚蛋白。
DOI：
10.1083/jcb.201503088
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发表时间：
2015-08-17
期刊：
影响因子：
--
通讯作者：
Emr SD
中科院分区：
文献类型：
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作者：
Henne WM;Zhu L;Balogi Z;Stefan C;Pleiss JA;Emr SD
Mdm1是一种定位于酵母菌内质网液泡/溶酶体连接处的新型细胞器间系泊蛋白，Mdm1的截断类似于疾病相关的Snx14等位基因，不能系泊内质网和液泡，也不能扰乱鞘脂代谢。虽然内溶酶体运输是明确的，但它是如何调节和协调细胞代谢尚不清楚。为了确定控制内溶酶体动力学的基因，我们进行了一项基于荧光的全球筛选，以揭示膜效应基因。筛选涉及Phox （PX）结构域蛋白Mdm1在膜动力学。令人惊讶的是，我们证明Mdm1是一种新的细胞器间系泊蛋白，定位于内质网(ER) -液泡/溶酶体膜接触位点（MCSs）。我们发现Mdm1是内质网锚定的，并通过其脂质结合的PX结构域以反式方式与液泡表面接触。引人注目的是，Mdm1的过表达诱导er液泡超栓系，强调其作为细胞器间栓系的作用。我们还发现Mdm1及其旁系物Ydr179w-a（在本研究中命名为Nvj3）独立于已建立的系链Nvj1定位于er液泡mcs。最后，我们发现Mdm1的截断类似于神经疾病相关的SNX14等位基因，不能束缚内质网和液泡，也不能扰乱鞘脂代谢。我们的研究表明，人类Mdm1同源物可能在细胞器间通讯和脂质代谢中发挥了以前未被认识到的作用。
Mdm1 is a novel interorganelle tethering protein that localizes to yeast ER–vacuole/lysosome junctions, and Mdm1 truncations analogous to disease-associated Snx14 alleles fail to tether the ER and vacuole and perturb sphingolipid metabolism. Although endolysosomal trafficking is well defined, how it is regulated and coordinates with cellular metabolism is unclear. To identify genes governing endolysosomal dynamics, we conducted a global fluorescence-based screen to reveal endomembrane effector genes. Screening implicated Phox (PX) domain–containing protein Mdm1 in endomembrane dynamics. Surprisingly, we demonstrate that Mdm1 is a novel interorganelle tethering protein that localizes to endoplasmic reticulum (ER)–vacuole/lysosome membrane contact sites (MCSs). We show that Mdm1 is ER anchored and contacts the vacuole surface in trans via its lipid-binding PX domain. Strikingly, overexpression of Mdm1 induced ER–vacuole hypertethering, underscoring its role as an interorganelle tether. We also show that Mdm1 and its paralogue Ydr179w-a (named Nvj3 in this study) localize to ER–vacuole MCSs independently of established tether Nvj1. Finally, we find that Mdm1 truncations analogous to neurological disease–associated SNX14 alleles fail to tether the ER and vacuole and perturb sphingolipid metabolism. Our work suggests that human Mdm1 homologues may play previously unappreciated roles in interorganelle communication and lipid metabolism.