Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability

Tobias G. Schips, Davy Vanhoutte, Alexander Vo, Robert N. Correll, Matthew J. Brody, Hadi Khalil, Jason Karch, Andoria Tjondrokoesoemo, Michelle A. Sargent, Marjorie Maillet, Robert S. Ross and Jeffery D. Molkentin ()
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Tobias G. Schips: Cincinnati Children’s Hospital Medical Center
Davy Vanhoutte: Cincinnati Children’s Hospital Medical Center
Alexander Vo: Cincinnati Children’s Hospital Medical Center
Robert N. Correll: Cincinnati Children’s Hospital Medical Center
Matthew J. Brody: Cincinnati Children’s Hospital Medical Center
Hadi Khalil: Cincinnati Children’s Hospital Medical Center
Jason Karch: Cincinnati Children’s Hospital Medical Center
Andoria Tjondrokoesoemo: Cincinnati Children’s Hospital Medical Center
Michelle A. Sargent: Cincinnati Children’s Hospital Medical Center
Marjorie Maillet: Cincinnati Children’s Hospital Medical Center
Robert S. Ross: University of California at San Diego School of Medicine
Jeffery D. Molkentin: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Thrombospondins (Thbs) are a family of five secreted matricellular glycoproteins in vertebrates that broadly affect cell-matrix interaction. While Thbs4 is known to protect striated muscle from disease by enhancing sarcolemmal stability through increased integrin and dystroglycan attachment complexes, here we show that Thbs3 antithetically promotes sarcolemmal destabilization by reducing integrin function, augmenting disease-induced decompensation. Deletion of Thbs3 in mice enhances integrin membrane expression and membrane stability, protecting the heart from disease stimuli. Transgene-mediated overexpression of α7β1D integrin in the heart ameliorates the disease predisposing effects of Thbs3 by augmenting sarcolemmal stability. Mechanistically, we show that mutating Thbs3 to contain the conserved RGD integrin binding domain normally found in Thbs4 and Thbs5 now rescues the defective expression of integrins on the sarcolemma. Thus, Thbs proteins mediate the intracellular processing of integrin plasma membrane attachment complexes to regulate the dynamics of cellular remodeling and membrane stability.

Date: 2019
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DOI: 10.1038/s41467-018-08026-8

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