Mycolactone subverts immunity by selectively blocking the Sec61 translocon

Area of Science:

• Molecular Biology
• Immunology
• Microbiology

Background:

• Mycolactone, an immunosuppressive macrolide from Mycobacterium ulcerans, is known to impair Sec61-dependent protein translocation.
• The precise molecular mechanism of mycolactone's action on protein translocation remained unidentified.

Purpose of the Study:

• To elucidate the molecular mechanism by which mycolactone impairs Sec61-dependent protein translocation.
• To identify the host receptor for mycolactone's immunomodulatory effects.

Main Methods:

• Directly assessing mycolactone's interaction with the Sec61 translocon.
• Utilizing site-directed mutagenesis to identify mycolactone-resistant Sec61 variants.
• Employing quantitative proteomics to analyze protein production changes in T cells.
• Evaluating the functional consequences of mycolactone-resistant Sec61 expression in immune cells.

Main Results:

• Mycolactone directly targets the alpha subunit of the Sec61 translocon, potently inhibiting the production of secreted and integral membrane proteins.
• A single amino acid mutation in Sec61α confers resistance to mycolactone, localizing the interaction site near the lumenal plug.
• Mycolactone-induced Sec61 blockade selectively impacts key signaling receptors and adhesion molecules during T cell activation.
• Expression of mycolactone-resistant Sec61α restored T cell homing and effector functions, and rescued antimicrobial responses in macrophages.

Conclusions:

• Sec61 is definitively identified as the host receptor mediating mycolactone's diverse immunomodulatory effects.
• Sec61 acts as a novel regulator of crucial immune cell functions, including T cell responses and macrophage antimicrobial activity.