TY - JOUR
T1 - A Cell-Intrinsic Interferon-like Response Links Replication Stress to Cellular Aging Caused by Progerin
AU - Kreienkamp, Ray
AU - Graziano, Simona
AU - Coll-Bonfill, Nuria
AU - Bedia-Diaz, Gonzalo
AU - Cybulla, Emily
AU - Vindigni, Alessandro
AU - Dorsett, Dale
AU - Kubben, Nard
AU - Batista, Luis Francisco Zirnberger
AU - Gonzalo, Susana
N1 - Publisher Copyright:
© 2018 The Authors
PY - 2018/2/20
Y1 - 2018/2/20
N2 - 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.
AB - 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.
KW - calcitriol
KW - interferon response
KW - lamins
KW - progeria
KW - replication stress
KW - reprogramming
UR - http://www.scopus.com/inward/record.url?scp=85042185919&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2018.01.090
DO - 10.1016/j.celrep.2018.01.090
M3 - Article
C2 - 29466729
AN - SCOPUS:85042185919
SN - 2211-1247
VL - 22
SP - 2006
EP - 2015
JO - Cell Reports
JF - Cell Reports
IS - 8
ER -