Mechanotransduction-induced interplay between phospholamban and yes-activated protein induces smooth muscle cell hypertrophy

Renee Rawson; Loan Duong; Eugene Tkachenko; Austin W T Chiang; Kevin Okamoto; Ranjan Dohil; Nathan E Lewis; Richard Kurten; Edsel M Abud; Seema S Aceves

doi:10.1016/j.mucimm.2024.02.007

Mechanotransduction-induced interplay between phospholamban and yes-activated protein induces smooth muscle cell hypertrophy

Mucosal Immunol. 2024 Feb 27:S1933-0219(24)00016-3. doi: 10.1016/j.mucimm.2024.02.007. Online ahead of print.

Authors

Affiliations

¹ Department of Pediatrics, University of California, San Diego, California; Division of Allergy Immunology, University of California, San Diego, California.
² Department of Pediatrics, University of California, San Diego, California; Division of Allergy Immunology, University of California, San Diego, California; Department of Medicine, University of California, San Diego, California.
³ Department of Pediatrics, University of California, San Diego, California; Department of Bioengineering, University of California, San Diego, California.
⁴ Department of Pediatrics, University of California, San Diego, California; Division of Gastroenterology, University of California, San Diego, California; XXX, Rady Children's Hospital, San Diego, California.
⁵ Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas; Department of Pediatrics, University of California, San Diego, California; Division of Allergy Immunology, University of California, San Diego, California.
⁶ Department of Pediatrics, University of California, San Diego, California; Division of Allergy Immunology, University of California, San Diego, California; XXX, Scripps Research Translational Institute, Scripps Research, San Diego, California.
⁷ Department of Pediatrics, University of California, San Diego, California; Division of Allergy Immunology, University of California, San Diego, California; XXX, Rady Children's Hospital, San Diego, California; Department of Medicine, University of California, San Diego, California. Electronic address: saceves@health.ucsd.edu.

PMID: 38423390
DOI: 10.1016/j.mucimm.2024.02.007

Abstract

The gastrointestinal system is a hollow organ affected by fibrostenotic diseases that cause volumetric compromise of the lumen via smooth muscle hypertrophy and fibrosis. Many of the driving mechanisms remain unclear. Yes-associated protein-1 (YAP) is a critical mechanosensory transcriptional regulator that mediates cell hypertrophy in response to elevated extracellular rigidity. In the type 2 inflammatory disorder, eosinophilic esophagitis (EoE), phospholamban (PLN) can induce smooth muscle cell hypertrophy. We used EoE as a disease model for understanding a mechanistic pathway in which PLN and YAP interact in response to rigid extracellular substrate to induce smooth muscle cell hypertrophy. PLN-induced YAP nuclear sequestration in a feed-forward loop caused increased cell size in response to a rigid substrate. This mechanism of rigidity sensing may have previously unappreciated clinical implications for PLN-expressing hollow systems such as the esophagus and heart.

Grants and funding

KL2 TR002552/TR/NCATS NIH HHS/United States