Ablation of CRBN induces loss of type I collagen and SCH in mouse skin by fibroblast senescence via the p38 MAPK pathway

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). The absence of cereblon in the skin of CRBN KO mice mimics the damage caused by narrowband ultraviolet B (NB-UVB). The primary CRBN deficient mouse embryonic fibroblasts (MEFs) undergo G2/M-arrested premature senescence via protein signaling of p38 MAPK and its dependent p53/p21pathway. The absence of CRBN induced the markers of cellular senescence, such as the senescence-associated heterochromatin foci (SAHF), SA-β-Gal staining, and p21 upregulation while the ectopic expression of CRBN reversed the phenotypes of SA-β-Gal staining and p21 upregulation. Reversion of the decreased protein level of collagen I was demonstrated after the reintroduction of the CRBN gene back into CRBN KO MEFs, validating the promising role of CRBN as a potential regulator for the function of the skin barrier and its cellular homeostasis.

The Inflamm-Aging Model Identifies Key Risk Factors in Atherosclerosis

“…The relationship pair with the greatest difference (0.08172) was CRBN–MRPL40 ( Table 5 ). CRBN functions as a potential regulator of cell homeostasis by mediating the ubiquitination of target substrates involved in processes including ion transport, the AMP-activated protein kinase (AMPK) signaling pathway, and cellular metabolisms ( Shi and Chen, 2017 ; Jeon et al, 2021 ). It also protects cells from fat metabolism disorders (induced by high-fat levels) and negatively regulates CD4 + T cell activation ( Shi and Chen, 2017 ), and has been implicated in a variety of diseases including CVD, obesity, and fatty liver ( Shi and Chen, 2017 ).…”

Comparative analysis of dermal collagen and lipids in cereblon ablated mice using a multimodal nonlinear optical system

“…Previously, we have shown that CRBN is a potential regulator of the skin barrier's function and dermal homeostasis, demonstrating a significant decrease in collagen I secretion into the extracellular space with an elevated protein expression of matrix metalloprotease 1 in CRBN KO mouse skin [8]. In addition, stratum corneum hydration (SCH) analyses revealed impaired skin barrier function caused by the loss of CRBN in the mouse skin tissues ex vivo [8]. Therefore, we further investigated the role of CRBN in mouse skin by optical assessment with second harmonic generation (SHG) microscopy, which is highly sensitive in detecting dermal collagen fibers in the skin.…”

“…We recently reported that CRBN is a potential regulator for skin barrier function and dermal homeostasis, revealing that the skin phenotype of CRBN ablated mice was similar to skin damaged by narrowband ultraviolet B (NB‐UVB). In detail, the CRBN ablated mice skin exhibited decreased protein expression of dermal collagen with altered protein signaling via cellular senescence in fibroblast [8]. In addition, CRBN deletion prevents high‐fat diet‐induced obesity in mice and exhibits noticeable changes in the gene expression of lipogenesis and lipid metabolism coordinated by AMP‐activated protein kinase(AMPK) [9].…”

Unripe Carica papaya Fresh Fruit Extract Protects against Methylglyoxal-Mediated Aging in Human Dermal Skin Fibroblasts

“…JNK transduces the signal to AP-1 and mediates MMP-3, IL-6, and IL-8 expression ( Song et al, 2019 ). p38 MAPK induces premature senescence phenotype in skin fibroblasts and downregulates COL1A1 ( Jeon et al, 2021 ). Like other natural substances from Dendrobium nobile Lindl., UCP withheld MGO-induced fibroblast senescence by suppressing the JNK/c-Jun/MMPs and p38/NF-κB/COL1A1 axes ( Bigot et al, 2012 ; Terazawa et al, 2021 ; Li et al, 2022 ).…”