A new research result from Yun Zhao research group “Sqh is involved in the regulation of Ci stability in Hh signaling pathway” is published online of Journal of Molecular Cell Biology and reveals the new role of Myosin light-chain protein SQH in Hh singling pathway.
Hedgehog (Hh) pathway is widely involved in cell growth and differentiation during both vertebrate and invertebrate development. The activity and stability of the key transcription factor, Ci/Gli, are regulated by Hh concentration, and further precisely induce downstream gene expressions. In the presence of Hh, full length Ci155 acts as a transcription activator，while in the absence of Hh, Ci155 is partially degraded into the truncated repressor form CiR (Ci75), which blocks downstream gene expressions, through Cul1-Slimb-based E3 ligase-mediated proteolysis. However, the studies about the molecular mechanism of partial degradation process from Ci155 to Ci75 and the regulation of the Ci stability are very limited currently.
To find out this mystery, postdoctoral Chunying Liu and employee Yue Xiong from Yun Zhao research group screened some candidate proteins and found SQH (CG3595), a myosin regulatory, which is involved in the regulation of Ci stability. Sqh not only protects Ci155 and Ci75 from degradation, but also promotes the processing from Ci155 to Ci75 in the presence of Hh. The phosphorylation of T20 and S21 on Sqh plays a critical role for its function and this process is regulated by Hh signal. Based on the study, they proposed a model that Sqh regulates Ci stability via keeping a dynamic balance between its phosphorylated and unphosphorylated forms. In the presence of Hh, phosphorylated Sqh interacts with Ci and recruits other degradation-related proteins to involve in Ci75 formation. Ci75 interacts with Sqh to protect Ci75 being further degraded. Under this condition, Ci75 level is increased, which restrains the over activation of Hh target genes. In the absence of Hh, Sqh cannot be phosphorylated. Unphosphorylated Sqh interacts with Ci and partially protects Ci155 from degradation. Under this condition, the formation of Ci75 is reduced, which prevents the over inhibition of Hh target genes. This study reveals SQH involved in Ci stability regulation in the Hh signaling pathway for the first time, helps understanding Hh pathway in more detail and gives an insight for related human diseases treatment.
AUTHOR CONTACT:
Zhao Yun, Principal Investigator
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Shanghai 200031, China
Phone: 021-54921618
E-mail: yunzhao@sibcb.ac.cn
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