Program Coordinator Hong Kong Univeristy of Science & Technology HKST, Hong Kong
Abstract: Adult muscle satellite cells (MuSCs) stay in a quiescent state in uninjured skeletal muscles under homeostasis. Upon muscle injury, MuSCs are rapidly activated, re-enter the cell cycle to proliferate, followed by differentiation and self-renewal to drive muscle regeneration. Paxbp1 was first identified as an adaptor protein linking the transcription factors Pax3 and Pax7 to a histone methyltransferase complex (Diao et al., Cell Stem Cell, 2012). Our subsequent work showed that it serves as a key regulator of a cell growth checkpoint during early activation of MuSCs. Specific deletion of Paxbp1 in adult MuSCs results in a cell-cycle re-entry failure and cell apoptosis during MuSC activation, leading to a total failure in muscle regeneration (Zhou et al., PNAS, 2021). However, it remains unclear how Paxbp1 exerts its functions in MuSCs. Through a BioID screening and confirmed by multiple assays, we identified Tfip11, a G-patch domain-containing nuclear protein implicated in RNA splicing, as a specific binding partner of Paxbp1. We found that Paxbp1 and Tfip11 stabilize each other in MuSCs: deletion of one protein quickly destabilized the other. Moreover, inducible deletion of Tfip11 in adult MuSCs also led to a cell-cycle re-entry failure and cell apoptosis, which recapitulated the phenotypes of Paxbp1-null MuSCs. Bioinformatic analysis of the transcriptomes of Paxbp1-null and Tfip11-null MuSCs confirmed that there were extensive yet overlapping RNA splicing defects in both types of mutant MuSCs. Lastly, we provide experimental evidence suggesting that Paxbp1 and Tfip11 are dynamic components of several distinct spliceosome complexes. Collectively, we demonstrate that Paxbp1 and Tfip11 not only physically bind to each other but also function together to regulate RNA splicing in adult MuSCs.
Funding Source: Research grant 16101323, 16104724, C6018-19G, T13-605/18W, T13-602/21-N, C6001-21E from the Hong Kong Research Grant Council, the Innovation and Technology Commission ITCPD/17-9, and the Shenzhen Bay Laboratory S201101002 China
