Gain and loss of the centrosomal protein taxilin-beta influences cardiac proteostasis and stress

Abstract

Centrosomes localize to perinuclear foci where they serve multifunctional roles, arranging the microtubule organizing center (MTOC) and anchoring ubiquitin proteasome system (UPS) machinery, as suggested by prior studies. In mature cardiomyocytes, centrosomal proteins redistribute into a specialized perinuclear cage-like structure, and a potential centrosomal-UPS interface has not been studied, despite established roles for UPS in cardiomyopathy. In addition, there have been no reports citing cardiomyocyte UPS dysfunction upon or after manipulation of centrosomal proteins. Taxilin-beta (Txlnb), a cardiomyocyte-enriched protein, belongs to a family of centrosome adapter proteins implicated in protein quality control. We hypothesize that Txlnb is part of the perinuclear centrosomal cage and regulates proteostasis in cardiomyocytes. Herein, we show that centrosome proteins, including Txlnb, have significantly broadly dysregulated RNA expressions in failing hearts; however, Txlnb protein levels appear to be unchanged. Reanalysis of Txlnb's interactome supports its involvement in cytoskeletal, microtubule, and UPS processes, particularly centrosome-related functions. Using gain and loss of function approaches, in cells and mice, we show that Txlnb is a novel regulator of cardiac proteostasis through its influence on UPS. Overexpressing Txlnb in cardiomyocytes reduces ubiquitinated protein accumulation and enhances proteasome activity during hypertrophy. Germline Txlnb knockout in mice increases ubiquitinated protein accumulation, decreases 26Sβ5 proteasome activity, and lowers cardiac mass with aging, indicating proteasomal insufficiency and altered cardiac growth. Loss of Txlnb worsens heart phenotypes in mouse models of cardiac proteotoxicity and pressure overload. Overall, our data implicate the centrosomal protein Txlnb as a novel regulator of cardiac proteostasis, highlighting the likely presence of an understudied and important centrosome-proteasome functional connection in cardiomyocytes.