P97/VCP (CDC48p in yeast) is a highly abundant molecular chaperone that functions in diverse cellular processes such as ubiquitin-dependent proteolysis, retrograde transport of protein from the endoplasmic reticulum (ER), cell cycle progression, DNA replication, chromosome condensation, and autophagy 1, 2, 3. In conclusion, SVIP is a novel regulator of adrenal cortisol and DHEA biosynthesis, suggesting that alterations in SVIP expression levels may be involved in the deregulation of steroidogenic stimulator signaling and abnormal adrenal hormone secretion. A certain degree of SVIP overexpression mainly increased the biosynthesis of cortisol as well as DHEA by enhancing the expression of key steroidogenic proteins, whereas exaggerated overexpression led to apoptosis, phosphorylation of eIF2α, and diminished adrenal steroid hormone biosynthesis. Interestingly, silencing of SVIP diminished cortisol secretion along with downregulation of steroidogenic enzymes and proteins involved in cholesterol uptake and cholesterol biosynthesis.

Steroidogenic stimulators caused a decrease in SVIP mRNA expression and increase in SVIP protein degradation in human adrenocortical H295R cells. We revealed that SVIP is highly expressed in the rat adrenal gland, especially in the cortex region, at a consistently high level during postnatal development, unlike the gradual increase in expression seen in developing nerves. As SVIP is a promising target for the regulation of ERAD, we aimed to assess its novel physiological roles. The multifunctionality of p97/VCP relies on its multiple binding partners, one of which is the endogenous ERAD inhibitor, SVIP (small VCP-interacting protein). Although the mechanism is complex, all ERAD branches converge on p97/VCP, a key protein in the retrotranslocation step.

The tight regulation of ERAD is critical for protein homeostasis as well as lipid metabolism.

Endoplasmic reticulum-associated degradation (ERAD) is a well-characterized mechanism of protein quality control by removal of misfolded or unfolded proteins.

Cortisol produced by adrenal cortex