Transcriptional, Post-Transcriptional, and Post-Translational Mechanisms Rewrite the Tubulin Code During Cardiac Hypertrophy and Failure

Frontiers in Cell and Developmental Biology

Kenneth Margulies²  Kenneth Bedi²  Joanna Griffin²  Sai Aung Phyo³  Christina Yingxian Chen³  Matthew A. Caporizzo³  Benjamin L. Prosser³  Keita Uchida³ 

[1] Department of Genetics and Epigenetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States;Department of Medicine, Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States;Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States;

关键词: hypertrophy;    heart failure;    tubulin isoforms;    transcription;    autoregulation;   

DOI  :  10.3389/fcell.2022.837486

来源: DOAJ

【 摘 要 】

A proliferated and post-translationally modified microtubule network underlies cellular growth in cardiac hypertrophy and contributes to contractile dysfunction in heart failure. Yet how the heart achieves this modified network is poorly understood. Determining how the “tubulin code”—the permutations of tubulin isoforms and post-translational modifications—is rewritten upon cardiac stress may provide new targets to modulate cardiac remodeling. Further, while tubulin can autoregulate its own expression, it is unknown if autoregulation is operant in the heart or tuned in response to stress. Here we use heart failure patient samples and murine models of cardiac remodeling to interrogate transcriptional, autoregulatory, and post-translational mechanisms that contribute to microtubule network remodeling at different stages of heart disease. We find that autoregulation is operant across tubulin isoforms in the heart and leads to an apparent disconnect in tubulin mRNA and protein levels in heart failure. We also find that within 4 h of a hypertrophic stimulus and prior to cardiac growth, microtubule detyrosination is rapidly induced to help stabilize the network. This occurs concomitant with rapid transcriptional and autoregulatory activation of specific tubulin isoforms and microtubule motors. Upon continued hypertrophic stimulation, there is an increase in post-translationally modified microtubule tracks and anterograde motors to support cardiac growth, while total tubulin content increases through progressive transcriptional and autoregulatory induction of tubulin isoforms. Our work provides a new model for how the tubulin code is rapidly rewritten to establish a proliferated, stable microtubule network that drives cardiac remodeling, and provides the first evidence of tunable tubulin autoregulation during pathological progression.

【 授权许可】

Unknown