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Native Polyacrylamide Gel Electrophoresis Immunoblot Analysis of Endogenous IRF5 Dimerization

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A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses.

Hui Zheng¹, Vibhor Gupta, Jeffrey Patterson-Fortin

¹Department of Animal Biology and Mari Lowe Comparative Oncology Center, School of Veterinary Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

|October 1, 2013

Summary

Serine hydroxymethyltransferase (SHMT) targets the BRISC deubiquitinating enzyme complex to Lys63-linked ubiquitin chains on the type 1 interferon receptor. This regulates interferon signaling and associated immunopathology, suggesting BRISC inhibitors as a therapeutic strategy.

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Area of Science:

Biochemistry
Molecular Biology
Immunology

Background:

Lysine63-linked ubiquitin (K63-Ub) chains are crucial signaling molecules.
Deubiquitinating enzymes (DUBs), like BRCC36, regulate K63-Ub chains.
BRCC36 exists in distinct complexes, including the BRISC complex, which lacks a known targeting moiety.

Purpose of the Study:

To identify the targeting moiety for the BRISC complex.
To elucidate the role of BRISC-SHMT complexes in interferon receptor regulation.
To investigate the therapeutic potential of targeting BRISC activity.

Main Methods:

Protein complex purification and characterization.
Ubiquitination and deubiquitination assays.
Cellular localization studies using microscopy.
Analysis of interferon signaling pathways in cells and animal models.

Main Results:

Serine hydroxymethyltransferase (SHMT) was identified as a component targeting BRISC to K63-Ub chains.
SHMT directs BRISC to deubiquitinate the type 1 interferon receptor chain 1 (IFNAR1).
BRISC-SHMT2 complexes limit IFNAR1 internalization and degradation, modulating interferon responses.
BRISC deficiency protects against IFN-associated immunopathology.

Conclusions:

SHMT is a novel targeting factor for the BRISC deubiquitinating enzyme.
BRISC-SHMT2 regulates interferon receptor signaling by controlling IFNAR1 ubiquitination.
Targeting BRISC may offer a therapeutic strategy for inflammatory conditions driven by excessive interferon signaling.