Sapkota lab publishes paper describing role of deubiquitylating enzyme USP15 on bone morphogenetic protein (BMP) signalling

Congratulations to Lina Herhaus and Mazin Al-Salihi, of Gopal Sapkota's lab, for publishing a paper in Open Biology that describes how USP15 regulates the BMP pathway by deubiquitylating the type I BMP receptor, ALK3.



BMPs belong to the transforming growth factor Ã_Â_ (TGFÃ_Â_) family of cytokines and play fundamental roles in development and tissue homeostasis. BMPs control many cellular processes, including proliferation, differentiation and morphogenesis. Therefore, abnormal BMP signalling is associated with several human diseases, including bone defects and cancer. Protein kinase ALK3 mediates BMP signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. This paper describes the identification of the deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3 and a regulator of BMP signalling. USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3, while mitigating the inhibition of BMP signalling caused by SMAD6. Consequently, the depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and inhibits both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. Furthermore, loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation.

Consistent with the findings in human and mouse cells (mostly Lina's and Mazin's efforts), Kevin Dingwell (Jim Smith's laboratory at NIMR, London) demonstrated that xUSP15 also modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis.

This paper was a mammoth effort by everyone in Gopal's lab, with contributions made also by Tim Cummins, Janis Vogt, Lize Wasmus and David Bruce. Richard Ewan, Thomas Macartney and Simone Weidlich also contributed to the paper. Collaborators Kevin Dingwell and Jim Smith (NIMR, London) contributed substantially to this work.

The paper entitled 'USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling' is available via Open Biology.