The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins
- University of California, San Francisco, United States
- Max Planck Institute of Biochemistry, Germany
- University of Pittsburgh, United States
Abstract
The endoplasmic reticulum (ER) supports biosynthesis of proteins with diverse transmembrane domain (TMD) lengths and hydrophobicity. Features in transmembrane domains such as charged residues in ion channels are often functionally important, but could pose a challenge during cotranslational membrane insertion and folding. Our systematic proteomic approaches in both yeast and human cells revealed that the ER membrane protein complex (EMC) binds to and promotes the biogenesis of a range of multipass transmembrane proteins, with a particular enrichment for transporters. Proximity-specific ribosome profiling demonstrates that the EMC engages clients cotranslationally and immediately following clusters of TMDs enriched for charged residues. The EMC can remain associated after completion of translation, which both protects clients from premature degradation and allows recruitment of substrate-specific and general chaperones. Thus, the EMC broadly enables the biogenesis of multipass transmembrane proteins containing destabilizing features, thereby mitigating the trade-off between function and stability.
Data availability
Sequencing data have been deposited in GEO under accession code GSE112891.
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The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteinsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE112891).
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The SND proteins constitute an alternative targeting route to the endoplasmic reticulumPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE85686).
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Principles of ER Co-Translational Translocation Revealed by Proximity-Specific Ribosome ProfilingPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE61012).
Article and author information
Author details
Jonathan S Weissman
Funding
Howard Hughes Medical Institute (Investigator Program)
- Jonathan S Weissman
Deutsche Forschungsgemeinschaft (Gottfried Wilhelm Leibniz Prize MA 1764/2-1)
- Georg HH Borner
European Research Council (ERC2012-SyG_318987-ToPAG)
- Daniel N Itzhak
Howard Hughes Medical Institute (Faculty Scholar Grant)
- Adam Frost
National Institutes of Health (AG041826)
- Jonathan S Weissman
National Institutes of Health (1DP2GM110772-01)
- Adam Frost
National Institutes of Health (8P41GM103481)
- Alma L Burlingame
National Institutes of Health (1S10OD16229)
- Alma L Burlingame
National Institutes of Health (GM075061)
- Jeffrey Brodsky
Helen Hay Whitney Foundation (Postdoctoral Fellowship)
- Matthew J Shurtleff
Jane Coffin Childs Memorial Fund for Medical Research (Postdoctoral Fellowship)
- Nicole T Schirle Oakdale
Sandler Foundation (Program for Breakthrough Biomedical Research)
- Adam Frost
American Asthma Foundation
- Adam Frost
Louis-Jeantet Foundation
- Daniel N Itzhak
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Alma L Burlingame
Max Planck Society for the Advancement of Science
- Daniel N Itzhak
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Shurtleff et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins
eLife 7:e37018.
https://doi.org/10.7554/eLife.37018
Further reading
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- Cell Biology
- Developmental Biology
Long thought to have little relevance to ovarian physiology, the rete ovarii may have a role in follicular dynamics and reproductive health.
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- Cell Biology
- Developmental Biology
The rete ovarii (RO) is an appendage of the ovary that has been given little attention. Although the RO appears in drawings of the ovary in early versions of Gray’s Anatomy, it disappeared from recent textbooks, and is often dismissed as a functionless vestige in the adult ovary. Using PAX8 immunostaining and confocal microscopy, we characterized the fetal development of the RO in the context of the mouse ovary. The RO consists of three distinct regions that persist in adult life, the intraovarian rete (IOR), the extraovarian rete (EOR), and the connecting rete (CR). While the cells of the IOR appear to form solid cords within the ovary, the EOR rapidly develops into a convoluted tubular epithelium ending in a distal dilated tip. Cells of the EOR are ciliated and exhibit cellular trafficking capabilities. The CR, connecting the EOR to the IOR, gradually acquires tubular epithelial characteristics by birth. Using microinjections into the distal dilated tip of the EOR, we found that luminal contents flow toward the ovary. Mass spectrometry revealed that the EOR lumen contains secreted proteins potentially important for ovarian function. We show that the cells of the EOR are closely associated with vasculature and macrophages, and are contacted by neuronal projections, consistent with a role as a sensory appendage of the ovary. The direct proximity of the RO to the ovary and its integration with the extraovarian landscape suggest that it plays an important role in ovary development and homeostasis.
