Innate Immune Signaling in is Regulated by Transforming Growth Factor β (TGFβ)-activated Kinase (Tak1)-triggered Ubiquitin Editing

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2017 Apr 6

PMID 28377500

Citations 17

Authors

Li Chen

Nicholas Paquette

Shahan Mamoor

Florentina Rus

Anubhab Nandy

John Leszyk

Scott A Shaffer

Neal Silverman

Affiliations

Soon will be listed here.

Abstract

Coordinated regulation of innate immune responses is necessary in all metazoans. In the Imd pathway detects Gram-negative bacterial infections through recognition of diaminopimelic acid (DAP)-type peptidoglycan and activation of the NF-κB precursor Relish, which drives robust antimicrobial peptide gene expression. Imd is a receptor-proximal adaptor protein homologous to mammalian RIP1 that is regulated by proteolytic cleavage and Lys-63-polyubiquitination. However, the precise events and molecular mechanisms that control the post-translational modification of Imd remain unclear. Here, we demonstrate that Imd is rapidly Lys-63-polyubiquitinated at lysine residues 137 and 153 by the sequential action of two E2 enzymes, Ubc5 and Ubc13-Uev1a, in conjunction with the E3 ligase Diap2. Lys-63-ubiquitination activates the TGFβ-activated kinase (Tak1), which feeds back to phosphorylate Imd, triggering the removal of Lys-63 chains and the addition of Lys-48 polyubiquitin. This ubiquitin-editing process results in the proteasomal degradation of Imd, which we propose functions to restore homeostasis to the immune response.

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