Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy
| Autor: | Kelly M. Grimes, Michelle A. Sargent, Alexander Vo, Davy Vanhoutte, Tobias G. Schips, Tanya A. Baldwin, Matthew J. Brody, Jeffery D. Molkentin, Federica Accornero |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Chaperone-mediated autophagy CD36 Science Eukaryotic Initiation Factor-2 Cardiology General Physics and Astronomy Gene Expression Cardiomegaly Mice Transgenic 030204 cardiovascular system & hematology Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences eIF-2 Kinase 0302 clinical medicine Atrophy medicine Autophagy Animals Myocytes Cardiac Pressure overload Thrombospondin Multidisciplinary Endoplasmic reticulum CD47 Myocardium ATF4 General Chemistry medicine.disease Endoplasmic Reticulum Stress Activating Transcription Factor 4 Cell biology 030104 developmental biology Proteolysis biology.protein Lysosomes Thrombospondins |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021) |
| ISSN: | 2041-1723 |
| Popis: | 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. Beneficial and detrimental effects have been ascribed to the different Thrombospondin (Thbs) proteins in the adult mammalian heart. Here, the authors show that Thbs1-mediated activation of PERK-eIF2α-ATF4-induced autophagy regulates adult cardiomyocyte size in the stressed heart. |
| Databáze: | OpenAIRE |
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