Age-Onset Phosphorylation of a Minor Actin Variant Promotes Intestinal Barrier Dysfunction

• Published in: Developmental cell Vol. 51; no. 5; pp. 587 - 601.e7
• Main Authors: Egge, Nathan, Arneaud, Sonja L.B., Wales, Pauline, Mihelakis, Melina, McClendon, Jacob, Fonseca, Rene Solano, Savelle, Charles, Gonzalez, Ian, Ghorashi, Atossa, Yadavalli, Sivaramakrishna, Lehman, William J., Mirzaei, Hamid, Douglas, Peter M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.12.2019
• Subjects: actin; aging; barrier; HSF-1; intestine; junctions; kinase; pathogenesis; phosphorylation; stress; pathogenesis; stress; HSF-1; actin; kinase; intestine; barrier; aging; phosphorylation; junctions
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2019.11.001

Age-associated decay of intercellular interactions impairs the cells’ capacity to tightly associate within tissues and form a functional barrier. This barrier dysfunction compromises organ physiology and contributes to systemic failure. The actin cytoskeleton represents a key determinant in maintaining tissue architecture. Yet, it is unclear how age disrupts the actin cytoskeleton and how this, in turn, promotes mortality. Here, we show that an uncharacterized phosphorylation of a low-abundant actin variant, ACT-5, compromises integrity of the C. elegans intestinal barrier and accelerates pathogenesis. Age-related loss of the heat-shock transcription factor, HSF-1, disrupts the JUN kinase and protein phosphatase I equilibrium which increases ACT-5 phosphorylation within its troponin binding site. Phosphorylated ACT-5 accelerates decay of the intestinal subapical terminal web and impairs its interactions with cell junctions. This compromises barrier integrity, promotes pathogenesis, and drives mortality. Thus, we provide the molecular mechanism by which age-associated loss of specialized actin networks impacts tissue integrity. [Display omitted] •The low-abundant, intestine-specific actin (ACT-5) affects animal aging•ACT-5 phosphorylation within its troponin binding site destabilizes actin networks•The Jun kinase (KGB-1) and PP1 phosphatase (GSP-1) regulate ACT-5 phosphorylation•Repression of KGB-1 by HSF-1 impacts the intestinal barrier and pathogenesis Aging is accompanied by a general loss of organ integrity. In the intestine, this “leakiness” can lead to infection, inflammation, and disease. Herein, Egge et al. uncover how dysregulation of a major structural component of cells, actin, leads to the loss of the intestine’s barrier and drives age and mortality.