Functional characterization of Cereblon as a novel modulator of cellular senescence and aging

Abstract

Cereblon (CRBN) is a substrate receptor of the cullin-RING E3 ubiquitin ligase (CRL) complex that mediates the ubiquitination of several substrates. In this study, CRBN knockout (KO) mice exhibited decreased levels of stratum corneum hydration (SCH) and collagen I expression with an elevated protein level of matrix metalloprotease 1 (MMP1) which is the senescence-associated secretory phenotype (SASP). The absence of Crbn in the skin of mice mimics the damage caused by narrowband ultraviolet B (NB-UVB) that is known to cause the aging process. Crbn-deficiency accelerates cell proliferation in primary mouse embryonic fibroblasts (MEFs). Ablation of CRBN showed a high level of cellular reactive oxygen species (ROS) and resistance to hydrogen peroxide (H2O2) treatment. Moreover, the NADPH pool altered by Crbn via upregulation of Glucose 6-phosphate dehydrogenase (G6PD) facilitates adaptation to ROS in MEFs. Since then, Crbn-deficient MEFs undergo G2/M-arrested premature senescence with the markers of cellular senescence such as the SA-β-Gal, senescence-associated heterochromatin foci (SAHF), p21, and p27 while the reintroduction of the crbn gene back into cells reversed the markers. The data obtained from this study improve an understanding of the physiological role of CRBN as a potential regulator for cellular senescence and the function of the skin barrier.