SUMOylation in Skeletal Development, Homeostasis, and Disease

Abstract

The modification of proteins by small ubiquitin-related modifier (SUMO) molecules, SUMOylation, is a key post-translational modification involved in a variety of biological processes, such as chromosome organization, DNA replication and repair, transcription, nuclear transport, and cell signaling transduction. In recent years, emerging evidence has shown that SUMOylation regulates the development and homeostasis of the skeletal system, with its dysregulation causing skeletal diseases, suggesting that SUMOylation pathways may serve as a promising therapeutic target. In this review, we summarize the current understanding of the molecular mechanisms by which SUMOylation pathways regulate skeletal cells in physiological and disease contexts.

Keywords: MSC; SUMO; arthritis; chondrocyte; developmental disorders; osteoblast; osteoclast; osteosarcoma; signaling pathway.

Figure 1

The enzymatic process of protein SUMOylation and deSUMOylation. (1) The nascent SUMO precursor protein is proteolytically cleaved to expose its C-terminal Gly-Gly motif by SENPs. (2) Mature SUMO is then activated by a heterodimer consistent of SAE1 and SAE2, the E1 complex, in an ATP dependent reaction, resulting in the formation of a thioester bond between SUMO and SAE2. (3) The activated SUMO is transferred to the E2 enzyme, UBC9. (4) With or without the help of an E3 ligase, UBC9 conjugates the SUMO group to the substrate protein by forming an isopeptide bond on a Lys residue. (5) SUMO modifications are removed from the target protein by SENPs.

Figure 2

Examples of SUMOylation pathways in skeletal physiology: (A) SENP6 maintains proper skeletal cell homeostasis during skeletal development and aging via regulating the TRIM28/P53 axis. OCP: osteochondroprogenitor. (B) SUMOylation of androgen receptor (AR) increases osteoblast (OB) number and bone formation; SENP3 suppresses osteoclast (OC) formation by deSUMOylating IRF8.

Figure 3

Examples of SUMOylation pathways in skeletal disease: (A) SENP3 overexpression upregulates osteoarthritis markers. SUMOylation of ELK1 and IRF1 prevent cartilage matrix degradation in osteoarthritis. SUMOylation of S100A4 results in the activation of MMP13. (B) A balanced chromosomal translocation that results in SUMO1 haploinsufficiency is associated with non-syndromic cleft lip with or without cleft palate (NSCLP). SUMO1 polymorphisms are associated with cleft lip with or without cleft palate, cleft palate only or NSCLP. (C) SENP1 prevents rheumatoid arthritis (RA) through deSUMOylating nuclear promyelocytic leukemia (PML) nuclear bodies and inhibits synoviocyte apoptosis. SENP1 attenuates rheumatoid arthritis by suppressing MMP1 expression. SUMOylation of Rac1 by PIAS3 promotes rheumatoid arthritis. SUMOylation of PKM2 induces synovial glycolysis and joint inflammation. UBC9 promotes rheumatoid arthritis by increasing the expression of MMPs. SUMO2 acts as an anti-inflammatory factor by preventing TNF-α stimulated expression of MMPs. (D) SENP5 is required for cell growth and apoptosis of osteosarcoma. SENP1 represses osteosarcoma by reducing the stemness of osteosarcoma cells, while promoting osteosarcoma by upregulating HIF-1α. SENP2 acts as an osteosarcoma suppressor by destabilizing SOX9. DeSUMOylation of connexin 43 (CX43) promotes gap-junction-mediated intercellular communication which sensitizes osteosarcomas cells to chemotherapy. SUMOylation of retinoic acid receptor α (RARα) is required for all-trans-retinoic acid (ATRA)-induced osteosarcoma cell differentiation.