Deubiquitination of RIPK2 by OTUB2 augments NOD2 signalling and protective effects in intestinal inflammation.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, but the molecular mechanisms underlying IBD are incompletely understood. In this study, we explored the role and regulating mechanism of otubain 2 (OTUB2), a deubiquitinating enzyme, in IBD. METHODS: To study the function of OTUB2 in IBD, we generated Otub2-/- mice and treated them with dextran sulfate sodium (DSS) to induce experimental colitis. Bone marrow transplantation was performed to identify the cell populations that were affected by OTUB2 in colitis. The molecular mechanism of OTUB2 in signal transduction was studied by various biochemical methods. RESULTS: OTUB2 was highly expressed in colon-infiltrating macrophages in both humans with IBD and mice with DSS-induced experimental colitis. Colitis was significantly aggravated in Otub2-/- mice and bone marrow chimeric mice receiving Otub2-/- bone marrow. OTUB2-deficiency impaired the production of cytokines and chemokines in macrophages in response to the NOD2 agonist muramyl dipeptide (MDP). Upon MDP stimulation, OTUB2 promoted NOD2 signaling by stabilizing RIPK2. Mechanistically, OTUB2 inhibited the proteasomal degradation of RIPK2 by removing K48-linked polyubiquitination on RIPK2, which was mediated by the active C51 residue in OTUB2. In mice, OTUB2 ablation abolished the protective effects of MDP administration in colitis. CONCLUSION: This study identified OTUB2 as a novel regulator of intestinal inflammation.

YOD1 sustains NOD2-mediated protective signaling in colitis by stabilizing RIPK2.

Inflammatory bowel disease (IBD) is a disorder causing chronic inflammation in the gastrointestinal tract, and its pathophysiological mechanisms are still under investigation. Here, we find that mice deficient of YOD1, a deubiquitinating enzyme, are highly susceptible to dextran sulfate sodium (DSS)-induced colitis. The bone marrow transplantation experiment reveals that YOD1 derived from hematopoietic cells inhibits DSS colitis. Moreover, YOD1 exerts its protective role by promoting nucleotide-binding oligomerization domain 2 (NOD2)-mediated physiological inflammation in macrophages. Mechanistically, YOD1 inhibits the proteasomal degradation of receptor-interacting serine/threonine kinase 2 (RIPK2) by reducing its K48 polyubiquitination, thereby increasing RIPK2 abundance to enhance NOD2 signaling. Consistently, the protective function of muramyldipeptide, a NOD2 ligand, in experimental colitis is abolished in mice deficient of YOD1. Importantly, YOD1 is upregulated in colon-infiltrating macrophages in patients with colitis. Collectively, this study identifies YOD1 as a novel regulator of colitis.

USP25 ameliorates diabetic nephropathy by inhibiting TRAF6-mediated inflammatory responses.

Diabetic kidney disease (DKD) is a common diabetic vascular complication affecting nearly 40% of patients with diabetes. The lack of efficacious therapy for DKD necessitates the in-depth investigation of the molecular mechanisms underlying the pathogenesis and progression of DKD, which remain incompletely understood. Here, we discovered that the expression of USP25, a deubiquitinating enzyme, was significantly upregulated in the kidney of diabetic mice. Ablation of USP25 had no influence on glycemic control in type 1 diabetes but significantly aggravated diabetes-induced renal dysfunction and fibrosis by exacerbating inflammation in the kidney. In DKD, USP25 was mainly expressed in glomerular mesangial cells and kidney-infiltrating macrophages. Upon stimulation with advanced glycation end-products (AGEs), USP25 markedly inhibited the production of proinflammatory cytokines in these two cell populations by downregulating AGEs-induced activation of NF-κB and MAPK pathways. Mechanistically, USP25 interacted with TRAF6 and inhibited its K63 polyubiquitination induced by AGEs. Collectively, these findings identify USP25 as a novel regulator of DKD.