A Protective Strategy against Hyperinflammatory Responses Requiring the Nontranscriptional Actions of GPS2

SummaryThe association between hyperinflammatory states and numerous diseases is widely recognized, but our understanding of the molecular strategies that have evolved to prevent uncontrolled activation of inflammatory responses remains incomplete. Here, we report a critical, nontranscriptional role of GPS2 as a guardian against hyperstimulation of the TNF-α-induced gene program. GPS2 cytoplasmic actions are required to specifically modulate RIP1 ubiquitylation and JNK activation by inhibiting TRAF2/Ubc13 enzymatic activity. In vivo relevance of GPS2 anti-inflammatory role is confirmed by inhibition of TNF-α target genes in macrophages and by improved insulin signaling in the adipose tissue of aP2-GPS2 transgenic mice. As the nontranscriptional role is complemented by GPS2 functioning as positive and negative cofactor for nuclear receptors, in vivo overexpression also results in elevated circulating level of Resistin and development of hepatic steatosis. Together, these studies define GPS2 as a molecular guardian required for precise control of inflammatory responses involved in immunity and homeostasis.

► GPS2 binds to the membrane TNFR1 complex and specifically regulates JNK activation
► GPS2 binds to TRAF2 and Ubc13 to inhibit their enzymatic activity
► In vivo overexpression of GPS2 inhibits proinflammatory responses
► Genome-wide genomic location analysis of GPS2/NCoR/TBL1