Transmembrane protein TMEM170A is a newly discovered regulator of ER and nuclear envelope morphogenesis in human cells

abstract: ...ABSTRACT The mechanism of endoplasmic reticulum (ER) morphogenesis is incompletely understood. ER tubules are shaped by the reticulons (RTNs) and DP1/Yop1p family members, but the mechanism of ER sheet formation is much less clear. Here, we characterize TMEM170A, a human transmembrane protein, which localizes in ER and nuclear envelope membranes. Silencing or overexpressing TMEM170A in HeLa K cells alters ER shape and morphology. Ultrastructural analysis reveals that downregulation of TMEM170A specifically induces tubular ER formation, whereas overexpression of TMEM170A induces ER sheet formation, indicating that TMEM170A is a newly discovered ER-sheet-promoting protein. Additionally, downregulation of TMEM170A alters nuclear shape and size, decreases the density of nuclear pore complexes (NPCs) in the nuclear envelope and causes either a reduction in inner nuclear membrane (INM) proteins or their relocalization to the ER. TMEM170A interacts with RTN4, a member of the reticulon family; simultaneous co-silencing of TMEM170A and RTN4 rescues ER, NPC and nuclear-envelope-related phenotypes, implying that the two proteins have antagonistic effects on ER membrane organization, and nuclear envelope and NPC formation.

...J Cell Sci J. Cell. Sci JCS joces Journal of Cell Science 0021-9533 1477-9137 The Company of Biologists Ltd 26906412 4852765 10.1242/jcs.175273 JCS175273 124 Research Article Transmembrane protein TMEM170A is a newly discovered regulator of ER and nuclear envelope morphogenesis in human cells Christodoulou Andri 1 Santarella-Mellwig Rachel 2 Santama Niovi 1 http://orcid.org/0000-0002-5537-8284 Mattaj Iain W. 2 * 1 Department of Biological Sciences , University of Cyprus , Nicosia , Cyprus 2

.... ABSTRACT The mechanism of endoplasmic reticulum (ER) morphogenesis is incompletely understood. ER tubules are shaped by the reticulons (RTNs) and DP1/Yop1p family members, but the mechanism of ER sheet formation is much less clear. Here, we characterize TMEM170A, a human transmembrane protein, which localizes in ER and nuclear envelope membranes. Silencing or overexpressing TMEM170A in HeLa K cells alters ER shape and morphology. Ultrastructural analysis reveals that downregulation of TMEM170A specifically induces tubular ER formation, whereas overexpression of TMEM170A induces ER sheet formation, indicating that TMEM170A is a newly discovered ER-sheet-promoting protein. Additionally, downregulation of TMEM170A alters nuclear shape and size, decreases the density of nuclear pore complexes (NPCs) in the nuclear envelope and causes either a reduction in inner nuclear membrane (INM) proteins or their relocalization to the ER. TMEM170A interacts with RTN4, a member of the reticulon family; simultaneous co-silencing of TMEM170A and RTN4 rescues ER, NPC and nuclear-envelope-related phenotypes, implying that the two proteins have antagonistic effects on ER membrane organization, and nuclear envelope and NPC formation. Highlighted Article: TMEM170A is a human ER and nuclear envelope transmembrane protein. Down- and overexpression induce tubular or sheet ER formation, respectively, indicating that TMEM170A is a newly discovered ER-sheet-promoting protein. KEY WORDS TMEM170A Reticulon Endoplasmic

... and maintained. In this work we identify and characterize TMEM170A, showing that it is a newly discovered ER-sheet-promoting protein whose concentration not only affects peripheral ER structure but also influences nuclear envelope expansion, NPC formation and INM protein targeting. In addition, we report that TMEM170A interacts with RTN4 and demonstrate that these two proteins act antagonistically on ER shape, and nuclear envelope and NPC formation. RESULTS Characterization of human TMEM170A protein The transmembrane protein TMEM170A is conserved in major eukaryotic phyla ( Fig.S1 ) but is thus far functionally uncharacterized. We identified human TMEM170A (Q8WVE7, UniProtKB/Swiss-Prot) as an ER and nuclear envelope protein in human cells through initial analysis of the location of transiently transfected TMEM170AGFP, FLAGTMEM170A or mycTMEM170A that, in all three cases, localized to both peripheral ER and nuclear envelope membranes ( Fig.1 Aac). We proceeded to generate a stably transfected HeLa K cell line expressing TMEM170A fused with GFP at its C-terminus. As expected, TMEM170AGFP was specifically located to ER and nuclear envelope membranes, extensively co-localized with the ER marker proteins calnexin and RNT4 ( Fig.1 Ad). Fig. 1. Localization and membrane topology of human TMEM170A. (A) TMEM170A localizes to the nuclear envelope and the ER. (Aac) Immunofluorescence of HeLa K cells transiently transfected with TMEM170AGFP (green), FLAGTMEM170A (green) or mycTMEM170A (red

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Gene: TMEM170A - transmembrane protein 170A - (NCBI)

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