Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy

Davy Vanhoutte,Tobias G Schips,Alexander Vo,Tanya A Baldwin,Michelle A Sargent,Federica Accornero,Jeffery D Molkentin,Matthew J Brody,Kelly M Grimes

doi:10.1038/s41467-021-24215-4

Abstract

The thrombospondin (Thbs) family of secreted matricellular proteins are stress- and injury-induced mediators of cellular attachment dynamics and extracellular matrix protein production. Here we show that Thbs1, but not Thbs2, Thbs3 or Thbs4, induces lethal cardiac atrophy when overexpressed. Mechanistically, Thbs1 binds and activates the endoplasmic reticulum stress effector PERK, inducing its downstream transcription factor ATF4 and causing lethal autophagy-mediated cardiac atrophy. Antithetically, Thbs1−/− mice develop greater cardiac hypertrophy with pressure overload stimulation and show reduced fasting-induced atrophy. Deletion of Thbs1 effectors/receptors, including ATF6α, CD36 or CD47 does not diminish Thbs1-dependent cardiac atrophy. However, deletion of the gene encoding PERK in Thbs1 transgenic mice blunts the induction of ATF4 and autophagy, and largely corrects the lethal cardiac atrophy. Finally, overexpression of PERK or ATF4 using AAV9 gene-transfer similarly promotes cardiac atrophy and lethality. Hence, we identified Thbs1-mediated PERK-eIF2α-ATF4-induced autophagy as a critical regulator of cardiomyocyte size in the stressed heart.

Highlights

The thrombospondin (Thbs) family of secreted matricellular proteins are stress- and injuryinduced mediators of cellular attachment dynamics and extracellular matrix protein production
The family of thrombospondin (Thbs) matricellular glycoproteins consists of five members (Thbs1-5), and while they are secreted as part of their life-cycle, they function as intracellular chaperones that mediate the endoplasmic reticulum (ER) stress response, facilitate secretory pathway activity and extracellular matrix production, and facilitate membrane residence of attachment complexes[8,9,10]
Single Thbs gene-deleted mice have been described with a wide variety of phenotypes, we recently showed that quintuple Thbs1/2/3/4/5−/− mice are viable as adults[9], highlighting the fact that these proteins primarily function in stress or injury resolution

Summary

Introduction

The thrombospondin (Thbs) family of secreted matricellular proteins are stress- and injuryinduced mediators of cellular attachment dynamics and extracellular matrix protein production. Thbs[1] binds and activates the endoplasmic reticulum stress effector PERK, inducing its downstream transcription factor ATF4 and causing lethal autophagy-mediated cardiac atrophy. Single Thbs gene-deleted mice have been described with a wide variety of phenotypes, we recently showed that quintuple Thbs1/2/3/4/5−/− mice are viable as adults[9], highlighting the fact that these proteins primarily function in stress or injury resolution In the heart, both Thbs[3] and Thbs[4] are induced with injury, yet overexpression of Thbs[4] is protective while Thbs[3] overexpression predisposes to disease with pressure overload stimulation[8,9,13]. We identify a Thbs1-mediated PERKeIF2α-ATF4-induced autophagy pathway as a fundamental regulator of protein homeostasis in the stressed heart

Methods

Results

Conclusion