A Cell-Intrinsic Interferon-like Response Links Replication Stress to Cellular Aging Caused by Progerin

Ray Kreienkamp, Simona Graziano, Nuria Coll-Bonfill, Gonzalo Bedia-Diaz, Emily Cybulla, Alessandro Vindigni, Dale Dorsett, Nard Kubben, Luis Francisco Zirnberger Batista, Susana Gonzalo

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by a truncated lamin A protein (progerin) that drives cellular and organismal decline. HGPS patient-derived fibroblasts accumulate genomic instability, but its underlying mechanisms and contribution to disease remain poorly understood. Here, we show that progerin-induced replication stress (RS) drives genomic instability by eliciting replication fork (RF) stalling and nuclease-mediated degradation. Rampant RS is accompanied by upregulation of the cGAS/STING cytosolic DNA sensing pathway and activation of a robust STAT1-regulated interferon (IFN)-like response. Reducing RS and the IFN-like response, especially with calcitriol, improves the fitness of progeria cells and increases the efficiency of cellular reprogramming. Importantly, other compounds that improve HGPS phenotypes reduce RS and the IFN-like response. Our study reveals mechanisms underlying progerin toxicity, including RS-induced genomic instability and activation of IFN-like responses, and their relevance for cellular decline in HGPS. Kreienkamp et al. reveal mechanisms underlying cellular decline in the premature aging disease Hutchinson-Gilford progeria syndrome. Progerin, the mutant protein that causes this disease, elicits replication stress and a cell-intrinsic innate immune response. The study identifies strategies, such as calcitriol, that rescue these phenotypes and rejuvenate progeria cells.

Original languageEnglish
Pages (from-to)2006-2015
Number of pages10
JournalCell Reports
Volume22
Issue number8
DOIs
StatePublished - Feb 20 2018

Keywords

  • calcitriol
  • interferon response
  • lamins
  • progeria
  • replication stress
  • reprogramming

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    Kreienkamp, R., Graziano, S., Coll-Bonfill, N., Bedia-Diaz, G., Cybulla, E., Vindigni, A., Dorsett, D., Kubben, N., Batista, L. F. Z., & Gonzalo, S. (2018). A Cell-Intrinsic Interferon-like Response Links Replication Stress to Cellular Aging Caused by Progerin. Cell Reports, 22(8), 2006-2015. https://doi.org/10.1016/j.celrep.2018.01.090