Latexin deficiency in mice up-regulates inflammation and aggravates colitis through HECTD1/Rps3/NF-κB pathway

Abstract

The function of Latexin (LXN) in inflammation has attracted attention. However, no data are available regarding its role in colitis. We report that LXN is a suppressor of colitis. LXN deficiency leads to the severity of colitis in DSS-induced mice, and LXN is required for the therapeutic effect of retinoic acid on colitis. Using a proteomics approach, we demonstrate that LXN interacts and forms a functional complex with HECTD1 (an E3 ubiquitin ligase) and ribosomal protein subunit3 (Rps3). IκBα is one of the substrates of HECTD1. Ectopic expression of LXN leads to IκBα accumulation in intestinal epithelial cells, however, LXN knockdown enhances the interaction of HECTD1 and Rps3, contributing to the ubiquitination degradation of IκBα, and subsequently enhances inflammatory response. Thus, our findings provided a novel mechanism underlying LXN modulates colitis via HECTD1/Rps3/NF-κB pathway and significant implications for the development of novel strategies for the treatment of colitis by targeting LXN.

Structural Insights into Ankyrin Repeat-Containing Proteins and Their Influence in Ubiquitylation

“…Specifically, HECTD1 mediates Iκβα K48 polyubiquitylation through its direct interaction with the ribosomal protein subunit 3 (Rsp3). HECTD1 forms a ternary complex with latexin (LAX), Iκβα and ribosomal protein subunit 3 (Rps3); this triggers Iκβα ubiquitylation and upregulates the NF-κβ stimulated inflammatory stress response [ 66 ]. Interestingly, only Rsp3 detachment from the complex attenuates LEX/HECTD1 interaction [ 66 ].…”

“…HECTD1 forms a ternary complex with latexin (LAX), Iκβα and ribosomal protein subunit 3 (Rps3); this triggers Iκβα ubiquitylation and upregulates the NF-κβ stimulated inflammatory stress response [ 66 ]. Interestingly, only Rsp3 detachment from the complex attenuates LEX/HECTD1 interaction [ 66 ]. Overall, the formation of the Rsp3/HECTD1 complex encourages ubiquitylation of Iκβα and LAX can competitively bind to the Rsp3 binding site to inhibit ubiquitylation.…”

Application of Genetic Algorithm-Based Support Vector Machine in Identification of Gene Expression Signatures for Psoriasis Classification: A Hybrid Model

“…The protein encoded by RPS3 has an important role in DNA repair through the cleavage of damaged DNA. Moreover, RPS3 enhances the inflammatory response through proteasomal degradation of I κ B α [ 39 , 40 ].…”

Involvement of HECTD1 in LPS-induced astrocyte activation via σ-1R-JNK/p38-FOXJ2 axis

“…Also, the cranial mesenchyme cell migration is correlated with HECTD1 expression [ 11 , 12 ]. Furthermore, interaction of HECTD1 with ribosomal protein subunit 3 contributes to degradation of IκBα, and subsequently facilitates inflammatory response [ 13 ]. Recent study demonstrated that HECTD1 is involved in regulation of microglia activation by promoting HSP90 degradation via ubiquitination, which implies the correlation between HECTD1 and inflammation in the CNS [ 14 ].…”

“…Recent study demonstrated that HECTD1 is involved in regulation of microglia activation by promoting HSP90 degradation via ubiquitination, which implies the correlation between HECTD1 and inflammation in the CNS [ 14 ]. Although the studies of HECTD1 in multiple cells have been conducted [ 8 ], the role of HECTD1 in astrocyte activation currently remains elusive [ 13 ].…”