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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
PubMed

Insights

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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