Nuclear Condensates Of Wac Regulate Mitophagy Through Alternative Splicing

The present study aimed to investigate the nuclear condensates formation ability of Desanto-Shinawi syndrome (DESSH) related protein-WW domain-containing adaptor with coiled-coil (WAC) and related biological function. The capacity of WAC to form nuclear condensates was investigated both in vivo and in vitro. Through RNA sequencing (RNA-seq) and immunoprecipitation-mass spectrometry (IP-MS), this study identified potential protein-protein interactions involving WAC condensates. WAC acts as a scaffold protein and facilitates the integration of RBM12 into nuclear speckles by forming nuclear condensate through its coiled-coil (CC) domain, where RBM12 potentially interacts with the spliceosomal U5 snRNP. Importantly, knockdown of RBM12, or deletion of the WAC CC domain led to alteredBECN1 splicing outcomes. The upregulated short splicing variant of BECN1 resulted in hyperactivated mitophagy. Our findings reveal a previously unrecognized mechanism for the nuclear regulation of mitophagy through liquid-liquid phase separation (LLPS) and provide insights into the pathogenesis of DESSH-related disorders.