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Secretory protein profiling reveals TNF-α inactivation by selective and promiscuous Sec61 modulators
Sarah V Maifeld1, Andrew L MacKinnon, Jennifer L Garrison
1Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Chemistry & Biology
|September 28, 2011
Summary
Cotransins, which target the Sec61 translocon, show altered substrate selectivity based on side-chain differences. This reveals new insights into cotransin-sensitive proteins, including tumor necrosis factor alpha (TNF-α).
Area of Science:
- Molecular Biology
- Cell Biology
- Protein Translocation
Background:
- Cotransins are cyclic heptadepsipeptides that inhibit protein translocation via the Sec61 translocon.
- Previously, cotransin sensitivity was linked to cleavable signal sequences targeting proteins to the translocon.
Purpose of the Study:
- To investigate how cotransin side-chain variations influence substrate selectivity.
- To identify new cotransin-sensitive proteins and understand their targeting mechanisms.
Main Methods:
- Profiling of two cotransin variants against a panel of secreted and transmembrane proteins.
- Analysis of protein targeting mechanisms, including signal sequences and membrane-spanning domains.
Main Results:
- Cotransin side-chain differences significantly impact substrate selectivity.
- Tumor necrosis factor alpha (TNF-α), a proinflammatory cytokine, was identified as a highly sensitive substrate.
- TNF-α, a type II transmembrane protein, is targeted to the translocon via its membrane-spanning domain, not a cleavable signal sequence.
Conclusions:
- A cleavable signal sequence is not strictly required for cotransin sensitivity.
- The study reveals a broader range of translocon substrates inhibited by Sec61 modulators than previously known.
- Cotransin variants offer a tool to modulate the expression of diverse proteins, including inflammatory cytokines.
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