Transforming growth factor-beta-independent regulation of myogenesis by SnoN sumoylation.
Recent progress has been made on the role of oncoproteins c-Ski and related SnoN in the control of cellular transformation. c-Ski/SnoN potently repress transforming growth factor-beta (TGF-beta) antiproliferative signaling through physical interaction with signal transducers called Smads. Overexpression of c-Ski/SnoN also induces skeletal muscle differentiation, but how c-Ski/SnoN function in myogenesis is largely unknown. During our investigation on the role of sumoylation in TGF-beta signaling, we inadvertently found that SnoN is modified by small ubiquitin-like modifier-1 (SUMO-1). Here, we biochemically characterize SnoN sumoylation in detail and report the physiological function of the modification. Sumoylation occurs primarily at lysine 50 (Lys-50). PIAS1 and PIASx proteins physically interact with SnoN to stimulate its sumoylation, thus serving as SUMO-protein isopeptide ligases (E3) for SnoN sumoylation. SnoN sumoylation does not alter its metabolic stability or its ability to repress TGF-beta signaling. Notably, loss of sumoylation in the Lys-50 site (via a Lys-to-Arg point mutation) potently activates muscle-specific gene expression and enhances myotube formation. Our study suggests a novel role for SUMO modification in the regulation of myogenic differentiation.
Wrighton
Katharine H
KH
Michael E. DeBakey Department of Surgery and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Liang
Min
M
Bryan
Brad
B
Luo
Kunxin
K
Liu
Mingyao
M
Feng
Xin-Hua
XH
Lin
Xia
X
D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008239:Lysine; D024510:Muscle Development; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000502:physiology*; D016212:Transforming Growth Factor beta; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D050828:Protein Inhibitors of Activated STAT; D011518:Proto-Oncogene Proteins; C060615:SKIL protein, human; D025842:SUMO-1 Protein; D016212:Transforming Growth Factor beta; D044767:Ubiquitin-Protein Ligases; D008239:Lysine