Volume 31, No 7, Jul 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 7, July 2021: 801-813   |  Open Access

ORIGINAL ARTICLES

The noncanonical role of the protease cathepsin D as a cofilin phosphatase

Yi-Jun Liu^1,2,* , Ting Zhang^1,2 , Sicong Chen³ , Daxiao Cheng^1,2 , Cunjin Wu² , Xingyue Wang^1,2 , Duo Duan² , Liya Zhu^1,2 , Huifang Lou^1,2 , Zhefeng Gong² , Xiao-Dong Wang^2,4,* , Margaret S. Ho^5,* , Shumin Duan^1,2

¹Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
²Research Units for Emotion and Emotion Disorders, NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China;
³Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
⁴Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China
⁵School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
These authors contributed equally: Yi-Jun Liu, Ting Zhang Correspondence: Yi-Jun Liu(yjliu@zju.edu.cn)Xiao-Dong Wang(xiaodongwang@zju.edu.cn)Margaret S. Ho(margareth@shanghaitech.edu.cn)

Cathepsin D (cathD) is traditionally regarded as a lysosomal protease that degrades substrates in acidic compartments. Here we report cathD plays an unconventional role as a cofilin phosphatase orchestrating actin remodeling. In neutral pH environments, the cathD precursor directly dephosphorylates and activates the actin-severing protein cofilin independent of its proteolytic activity, whereas mature cathD degrades cofilin in acidic pH conditions. During development, cathD complements the canonical cofilin phosphatase slingshot and regulates the morphogenesis of actin-based structures. Moreover, suppression of cathD phosphatase activity leads to defective actin organization and cytokinesis failure. Our findings identify cathD as a dual-function molecule, whose functional switch is regulated by environmental pH and its maturation state, and reveal a novel regulatory role of cathD in actin-based cellular processes.

https://doi.org/10.1038/s41422-020-00454-w

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