COP9 Signalosome is Required for Adipose Tissue Maintenance and Metabolic Health

COP9 (constitutive photomorphogenesis mutant 9) signalosome (CSN) is composed of eight subunits (CSN1 through CSN8). It acts as an essential regulator of Cullin-RING-ubiquitin ligases (CRLs), which target critical cellular regulators for degradation via the ubiquitin (Ub) proteasome pathway. The role of CSN in adipose tissue development and function has not yet been studied. We sought to determine the role of CSN8, the smallest subunit of the CSN complex, in adipogenesis, adipose tissue maintenance, and metabolic balance. In this study, we generated mice with adipocyte-specific deletion of CSN8 (Csn8AKO) and confirmed the deletion of CSN8 and the disruption of CSN holo-complex formation and Cullin deneddylation in white and brown adiposes. We performed bulk RNA-Seq and identified significant remodeling of white and brown adipose tissues, characterized by adipocyte cell death and inflammation. Specifically, white and brown adipose tissues lacking CSN8 exhibited marked upregulation of apoptotic and pyroptotic cell death, which was associated with alterations in ubiquitination and proteasome activity. Taken together, our data highlight that CSN8/CSN is crucial for maintaining protein homeostasis in adipose tissue, promoting adipocyte survival, supporting adipose tissue maintenance, and overall metabolic health. Overall design: We performed bulk RNA-Seq in subcutaneous adipose tissues from 12-week-old male wildtype (WT) and Csn8AKO (KO) mice (n=4/group), and brown adipose tissues from 4-week-old male WT and KO mice (n=5/group).