Abstract
The development, growth, and renewal of skeletal tissues rely on the function of osteochondroprogenitors (OCPs). Protein sumoylation/desumoylation has emerged as a pivotal mechanism for stem cell/progenitor homeostasis, and excessive sumoylation has been associated with cell senescence and tissue aging, but its role in regulating OCP function is unclear. Here we show that postnatal loss of the desumoylase SUMO1/sentrin-specific peptidase 6 (SENP6) causes premature aging. OCP-specific SENP6 knockout mice exhibit smaller skeletons, with elevated apoptosis and cell senescence in OCPs and chondrocytes. In Senp6‒/‒ cells, the two most significantly elevated pathways are p53 signaling and senescence-associated secreted phenotypes (SASP), and Trp53 loss partially rescues the skeletal and cellular phenotypes caused by Senp6 loss. Furthermore, SENP6 interacts with, desumoylates, and stabilizes TRIM28, suppressing p53 activity. Our data reveals a crucial role of the SENP6–p53 axis in maintaining OCP homeostasis during skeletal development.
Highlights
The development, growth, and renewal of skeletal tissues rely on the function of osteochondroprogenitors (OCPs)
We detected a significant age-related decrease of Senp[6] expression in bone marrow stromal cells (BMSCs), a cell population rich in mesenchymal stem cell/progenitors, suggesting that SENP6 levels may be associated with the homeostasis of mesenchymal stem cells/progenitors during aging (Fig. 1b)
We found that global deletion of Senp[6] in adult mice caused a distinctive premature-aging phenotype
Summary
The development, growth, and renewal of skeletal tissues rely on the function of osteochondroprogenitors (OCPs). Protein sumoylation/desumoylation has emerged as a pivotal mechanism for stem cell/progenitor homeostasis, and excessive sumoylation has been associated with cell senescence and tissue aging, but its role in regulating OCP function is unclear. Defective OCP maintenance is considered an important cause of skeletal aging, as the exhaustion of progenitors or stem cells is one of the ultimate culprits of tissue/organism aging[3]. Emerging evidence indicates that the components of the sumoylation/desumoylation machineries play important roles in stem cell and progenitor maintenance and in tissue aging. UBC9 inhibits bone morphogenetic protein (BMP)induced osteoblast differentiation in cultures partly by enhancing SMAD4 sumoylation[11], and SENP3 promotes osteogenesis by desumoylating RbBP5 to activate the expression of HOX genes[12]. We report that SENP6 is a crucial regulator of the aging process and OCP maintenance during skeletal development. We further found that SENP6 suppresses p53 activity through interacting with, desumoylating, and stabilizing TRIM28 (tripartite motif-containing 28; called KAP1 or TIF1β)
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