The E3 ligase TRIM13 restrains LPS-induced inflammation by reducing STIM1 abundance and the IRE1α-dependent unfolded protein response.
TL;DR
It is reported that the ER-localized E3 ubiquitin ligase TRIM13 restrained LPS-induced inflammatory responses in macrophages and in mice by protecting the cells from ER stress.
Abstract
Recognition of the bacterial product lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) initiates inflammatory responses. The unfolded protein response (UPR) elicited by endoplasmic reticulum (ER) stress can strengthen TLR4-dependent inflammatory responses. Here, we report that the ER-localized E3 ubiquitin ligase TRIM13 restrained LPS-induced inflammatory responses in macrophages and in mice by protecting the cells from ER stress. TRIM13 mediated Lys33-linked polyubiquitylation of the ER-localized Ca2+ sensor STIM1, promoting its degradation. TRIM13 deficiency caused STIM1 accumulation and activated store-operated Ca2+ entry (SOCE) and the inositol-requiring enzyme 1 α (IRE1α) branch of the UPR. Suppressing SOCE, chelating extracellular Ca2+, relieving ER stress, or blocking IRE1α activation inhibited the amplification of inflammatory responses caused by the loss of TRIM13 in macrophages. Pharmacological inhibition of IRE1α ameliorated chemically induced colitis in TRIM13-deficient mice. Our study suggests that TRIM13 restrains inflammation by limiting LPS-induced activation of SOCE and the IRE1α branch of the UPR.