Tissue‐Resident Macrophage‐Derived E3 Ligase SMURF2 Restricts Autoimmune Inflammation by Mediating the Degradation of p‐TBK1

Dysregulated Tissue resident macrophage (TRMs) link to autoimmune inflammation. SMURF2 mediates Lys‐27 (K27)‐linked ubiquitination of p‐TBK1 and its degradation, which inhibits CSF1R signaling‐triggered TRM proliferation, thereby restraining the autoimmune inflammation. Impaired expression of SMURF2 in TRM correlates with the progression of autoimmune disease in humans and mice. Abstract Dysregulated tissue‐resident macrophages (TRMs) contribute to the pathogenesis of inflammatory bowel disease (IBD) and multiple sclerosis (MS). Uncovering molecular regulators of the divergent role of TRMs in inflammation can advance therapeutic strategies for autoimmune disorders. Here, a significant downregulation of SMAD‐specific E3 ubiquitin protein ligase 2 (SMURF2) is reported in TRMs within inflamed intestinal tissues from both IBD patients and mouse models. Notably, TRM‐specific deficiency of Smurf2 significantly exacerbates TRM proliferation in dextran sulfate sodium (DSS)‐induced colitis and experimental autoimmune encephalomyelitis (EAE), leading to augmented autoimmune inflammation. Mechanistically, SMURF2 interacts with phosphorylated TBK1 (p‐TBK1), mediating its Lys‐27‐linked ubiquitination and its subsequent lysosomal degradation, thereby suppressing TRM proliferation and autoimmune inflammation. Collectively, these findings establish SMURF2 as a pivotal mediator of TRM proliferation and autoimmune inflammation via p‐TBK1 modulation. Given that impaired SMURF2 expression correlates with the progression of autoimmune inflammation, SMURF2 represents a potential target for autoimmune disease treatment. Dysregulated Tissue resident macrophage (TRMs) link to autoimmune inflammation. SMURF2 mediates Lys-27 (K27)-linked ubiquitination of p-TBK1 and its degradation, which inhibits CSF1R signaling-triggered TRM proliferation, thereby restraining the autoimmune inflammation. Impaired expression of SMURF2 in TRM correlates with the progression of autoimmune disease in humans and mice. Abstract Dysregulated tissue-resident macrophages (TRMs) contribute to the pathogenesis of inflammatory bowel disease (IBD) and multiple sclerosis (MS). Uncovering molecular regulators of the divergent role of TRMs in inflammation can advance therapeutic strategies for autoimmune disorders. Here, a significant downregulation of SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) is reported in TRMs within inflamed intestinal tissues from both IBD patients and mouse models. Notably, TRM-specific deficiency of Smurf2 significantly exacerbates TRM proliferation in dextran sulfate sodium (DSS)-induced colitis and experimental autoimmune encephalomyelitis (EAE), leading to augmented autoimmune inflammation. Mechanistically, SMURF2 interacts with phosphorylated TBK1 (p-TBK1), mediating its Lys-27-linked ubiquitination and its subsequent lysosomal degradation, thereby suppressing TRM proliferation and autoimmune inflammation. Collectively, these findings establish SMURF2 as a pivotal mediator of TRM proliferation and autoimmune inflammation via p-TBK1 modulation. Given that impaired SMURF2 expression correlates with the progression of autoimmune inflammation, SMURF2 represents a potential target for autoimmune disease treatment. Advanced Science, EarlyView.