Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, NSB#1, Rm. 5328, 9500 Gilman Drive, San Diego, CA 92093-0377, USA.
Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Rm. 6210, Chaoyang District, Beijing 100101, China.
Cell Rep. 2023 Dec 26;42(12):113403. doi: 10.1016/j.celrep.2023.113403. Epub 2023 Nov 17.
The inheritance of a functional endoplasmic reticulum (ER) is ensured by the ER stress surveillance (ERSU) pathway. Here, we made the unexpected discovery that reticulon 1 (Rtn1) and Yop1, well-known ER-curvature-generating proteins, each possess two sphingolipid-binding motifs within their transmembrane domains and that these motifs recognize the ER-stress-induced sphingolipid phytosphingosine (PHS), resulting in an ER inheritance block. Upon binding PHS, Rtn1/Yop1 accumulate on the ER tubule, poised to enter the emerging daughter cell, and cause its misdirection to the bud scars (i.e., previous cell division sites). Amino acid changes in the conserved PHS-binding motifs preclude Rtn1 or Yop1 from binding PHS and diminish their enrichment on the tubular ER, ultimately preventing the ER-stress-induced inheritance block. Conservation of these sphingolipid-binding motifs in human reticulons suggests that sphingolipid binding to Rtn1 and Yop1 represents an evolutionarily conserved mechanism that enables cells to respond to ER stress.
功能性内质网（ER）的遗传是通过内质网应激监测（ERSU）途径来保证的。在这里，我们有了一个意想不到的发现：内质网卷曲蛋白 1（Rtn1）和 Yop1，这两种都是众所周知的产生 ER 曲率的蛋白质，它们的跨膜结构域内都有两个神经酰胺结合基序，这些基序识别 ER 应激诱导的神经酰胺植烷醇（PHS），从而导致 ER 遗传受阻。在与 PHS 结合后，Rtn1/Yop1 在内质网管状结构上聚集，准备进入新出现的子细胞，并导致其错误地进入芽痕（即前一次细胞分裂的位点）。在保守的 PHS 结合基序中发生的氨基酸变化使 Rtn1 或 Yop1 无法与 PHS 结合，并减少它们在内质网管状结构上的富集，最终阻止了 ER 应激诱导的遗传受阻。这些神经酰胺结合基序在人类内质网卷曲蛋白中的保守性表明，Rtn1 和 Yop1 与神经酰胺的结合代表了一种进化上保守的机制，使细胞能够对内质网应激做出反应。
