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Background  The TM4 (UBAC2) protein, which contains 4 transmembrane domains and one ubiquitin binding domain, is mainly expressed in cell and nuclear membranes. The current research aimed to explore the role of  TM4  in metabolic inflammation and to examine whether the ubiquitin–proteasome inhibitor PS-341 could regulate the function of  TM4 .    Methods  The metabolic phenotypes of  TM4  knockout (KO) mice were studied. We next explored the association between the polymorphisms of  TM4  and obesity in a Chinese Han population.  TM4  expression in the visceral fat of obese patients who underwent laparoscopic cholecystectomy was also analysed. Finally, the effect of PS-341 on the degradation and function of the TM4 protein was investigated in vivo and in vitro.    Results   TM4  KO mice developed obesity, hepatosteatosis, hypertension, and glucose intolerance under a high-fat diet. TM4 counterregulated Nur77, IKKβ, and NF-kB both in vivo and in vitro. The  TM4  SNP rs147851454 is significantly associated with obesity after adjusting for age and sex ( OR  1.606, 95% CI 1.065–2.422  P  = 0.023) in 3394 non-diabetic and 1862 type 2 diabetic adults of Han Chinese.  TM4  was significantly downregulated in the visceral fat of obese patients. PS-341 induced TM4 expression through inhibition of TM4 degradation in vitro. In  db/db  mice, PS-341 administration led to downregulation of Nur77/IKKβ/NF-κB expression in visceral fat and liver, and alleviation of hyperglycaemia, hypertension, and glucose intolerance. The hyperinsulinaemic-euglycaemic clamp demonstrated that PS-341 improved the glucose infusion rate and alleviated insulin resistance in  db/db  mice.    Conclusions  PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through inhibition of TM4 degradation.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12986-021-00579-8.

PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through the inhibition of TM4 (UBAC2) degradation