Abstract P2064: A Specialized Centrosome-Proteasome Axis Mediates Proteostasis And Influences Cardiac Hypertrophy

Abstract

Mature cardiomyocytes (CMs) lack centrosomes. Instead, centriolar and satellite proteins redistribute into specialized perinuclear organelle-like compartments, where they likely serve multifunctional roles, e.g., in organizing microtubules and establishing localized clearance of aggregated/misfolded proteins via the ubiquitin-proteasome system (UPS). Taxilin-beta (Txlnb) is a CM-enriched protein that localizes perinuclear and belongs to the family of taxilin proteins, which are centrosomal proteins that have been implicated in protein quality control. We hypothesize that Txlnb plays key roles maintaining specialized centrosomal-proteasomal crosstalk in CMs. We first examined proteostatic roles for Txlnb in neonatal rat CMs treated with phenylephrine and found that Txlnb overexpression coordinately increased protein synthesis and proteasome activity, while decreasing ubiquitin-protein conjugate accumulation. We generated Txlnb knockout (Txlnb-KO) mice, which show robust accumulation of ubiquitinated proteins and decreased 26SB5 proteasome activity in heart tissues, as well as lower cardiac mass with aging. To test if Txlnb influences proteotoxic UPS dysfunction, we crossed Txlnb-KO mice to Cryab-R120G transgenic mice, a model of severe cardiac proteotoxicity with progression to heart failure and early death. Loss of Txlnb resulted in worsening of heart failure, evidenced by lower ejection fractions in Txlnb-KO/Cryab-R120G mice versus Cryab-R120G littermates. By contrast, AAV-mediated Txlnb overexpression in Cryab-R120G mice resulted in only slight reduction in myocardial wall thickness but was overall insufficient to slow heart failure progression. To test if Txlnb influences hypertrophic UPS dysfunction, Txlnb-KO and wildtype (WT) mice were subjected to cardiac pressure-overload induced by transverse aortic constriction (TAC). At 6-weeks post-TAC, Txlnb-KO mice showed reduced ejection fraction, increased heart mass, and elevated accumulation of ubiquitinated proteins, relative to WT mice. Together, these data provide initial evidence connecting Txlnb to proteostatic functions in cardiomyocytes, hinting at the potential importance of functional bridging between specialized centrosomes and UPS in CMs.