DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway.
Chronic inflammation in adipose tissue plays a key role in obesity-induced insulin resistance. However, the mechanisms underlying obesity-induced inflammation remain elusive. Here we show that obesity promotes mtDNA release into the cytosol, where it triggers inflammatory responses by activating the DNA-sensing cGAS-cGAMP-STING pathway. Fat-specific knockout of disulfide-bond A oxidoreductase-like protein (DsbA-L), a chaperone-like protein originally identified in the mitochondrial matrix, impaired mitochondrial function and promoted mtDNA release, leading to activation of the cGAS-cGAMP-STING pathway and inflammatory responses. Conversely, fat-specific overexpression of DsbA-L protected mice against high-fat diet-induced activation of the cGAS-cGAMP-STING pathway and inflammation. Taken together, we identify DsbA-L as a key molecule that maintains mitochondrial integrity. DsbA-L deficiency promotes inflammation and insulin resistance by activating the cGAS-cGAMP-STING pathway. Our study also reveals that, in addition to its well-characterized roles in innate immune surveillance, the cGAS-cGAMP-STING pathway plays an important role in mediating obesity-induced metabolic dysfunction.
['Bai|Juli|J|0000-0002-1193-8155', 'Cervantes|Christopher|C|', 'Liu|Juan|J|', 'He|Sijia|S|', 'Zhou|Haiyan|H|', 'Zhang|Bilin|B|', 'Cai|Huan|H|', 'Yin|Dongqing|D|', 'Hu|Derong|D|', 'Li|Zhi|Z|', 'Chen|Hongzhi|H|', 'Gao|Xiaoli|X|', 'Wang|Fang|F|', "O'Connor|Jason C|JC|", 'Xu|Yong|Y|', 'Liu|Meilian|M|', 'Dong|Lily Q|LQ|', 'Liu|Feng|F|0000-0002-5098-1711']
D041721:3T3-L1 Cells D017667:Adipocytes D000818:Animals D004272:DNA, Mitochondrial D059305:Diet, High-Fat D005786:Gene Expression Regulation D005982:Glutathione Transferase D006801:Humans D007249:Inflammation D007333:Insulin Resistance D008297:Male D008565:Membrane Proteins D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008928:Mitochondria D009713:Nucleotidyltransferases D009765:Obesity D061251:Primary Cell Culture D020033:Protein Isoforms D015398:Signal Transduction
DsbA-L inflammation insulin resistance obesity cGAS