USP2a Protein Deubiquitinates and Stabilizes the Circadian Protein CRY1 in Response to Inflammatory Signals
Year: 2012
Type: article
Abstract: The mammalian circadian clock coordinates various physiological activities with environmental cues to achieve optimal adaptation. The clock manifests oscillations of key clock proteins, which are under dynamic control at multiple post-translational levels. As a major post-translational regulator, the ubiquitination-dependent proteasome degradation system is counterbalanced by a large group of deubiquitin proteases with distinct substrate preference. Until now, whether deubiquitination by ubiquitin-specific proteases can regulate the clock protein stability and circadian pathways remains largely unclear. The mammalian clock protein, cryptochrome 1 (CRY1), is degraded via the FBXL3-mediated ubiquitination pathway, suggesting that it is also likely to be targeted by the deubiquitination pathway. Here, we identified that USP2a, a circadian-controlled deubiquitinating enzyme, interacts with CRY1 and enhances its protein stability via deubiquitination upon serum shock. Depletion of Usp2a by shRNA greatly enhances the ubiquitination of CRY1 and dampens the oscillation amplitude of the CRY1 protein during a circadian cycle. By stabilizing the CRY1 protein, USP2a represses the Per2 promoter activity as well as the endogenous Per2 gene expression. We also demonstrated that USP2a-dependent deubiquitination and stabilization of the CRY1 protein occur in the mouse liver. Interestingly, the pro-inflammatory cytokine, TNF-α, increases the CRY1 protein level and inhibits circadian gene expression in a USP2a-dependent fashion. Therefore, USP2a potentially mediates circadian disruption by suppressing the CRY1 degradation during inflammation.
Source: Journal of Biological Chemistry
Authors: Xin Tong, Katie Buelow, Anirvan Guha, Rebecca Rausch, Lei Yin
Institutions: University of Michigan, Michigan Medicine
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: G1947249616, Michigan Diabetes Research and Training Center, G5151584612, Interfacing computation and engineering with digestive and metabolic physiology, Biology of nuclear receptor Rev-erb alpha in circadian rhythm and metabolism, Biology of nuclear receptor rev-erb alpha in circadian rhythm and metabolism, Michigan Diabetes Research Center (MDRC)
OpenAlex ID: W2070861918