TY - JOUR
T1 - Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells
AU - Takahashi, Akiko
AU - Loo, Tze Mun
AU - Okada, Ryo
AU - Kamachi, Fumitaka
AU - Watanabe, Yoshihiro
AU - Wakita, Masahiro
AU - Watanabe, Sugiko
AU - Kawamoto, Shimpei
AU - Miyata, Kenichi
AU - Barber, Glen N.
AU - Ohtani, Naoko
AU - Hara, Eiji
N1 - Funding Information:
We thank the members of the Hara laboratory for helpful discussions during the preparation of this manuscript. This work was supported in part by grants from Japan Agency of Medical Research and Development (AMED) under grant number JP17gm5010001, 17gm0610002h0406, 17cm0106401h0002 and 17fk0210206h0002, Japan Science and Technology Agency (JST)-PRESTO under grant number JP1005462, Japan Society for the Promotion of Science (JSPS) under grant number 26250028, 25290046, 16H04700, 17K19618, 15K06942, and 15H01462, Uehara Memorial Foundation, Cell Science Research Foundation, Princess Takamatsu Cancer Research Fund, the Vehicle Racing Commemorative Foundation, The Naito Foundation, Takeda Science Foundation, and the Research Foundation for Microbial Diseases of Osaka University.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Accumulating evidence indicates that the senescence-associated secretory phenotype (SASP) contributes to many aspects of physiology and disease. Thus, controlling the SASP will have tremendous impacts on our health. However, our understanding of SASP regulation is far from complete. Here, we show that cytoplasmic accumulation of nuclear DNA plays key roles in the onset of SASP. Although both DNase2 and TREX1 rapidly remove the cytoplasmic DNA fragments emanating from the nucleus in pre-senescent cells, the expression of these DNases is downregulated in senescent cells, resulting in the cytoplasmic accumulation of nuclear DNA. This causes the aberrant activation of cGAS-STING cytoplasmic DNA sensors, provoking SASP through induction of interferon-β. Notably, the blockage of this pathway prevents SASP in senescent hepatic stellate cells, accompanied by a decline of obesity-associated hepatocellular carcinoma development in mice. These findings provide valuable new insights into the roles and mechanisms of SASP and possibilities for their control.
AB - Accumulating evidence indicates that the senescence-associated secretory phenotype (SASP) contributes to many aspects of physiology and disease. Thus, controlling the SASP will have tremendous impacts on our health. However, our understanding of SASP regulation is far from complete. Here, we show that cytoplasmic accumulation of nuclear DNA plays key roles in the onset of SASP. Although both DNase2 and TREX1 rapidly remove the cytoplasmic DNA fragments emanating from the nucleus in pre-senescent cells, the expression of these DNases is downregulated in senescent cells, resulting in the cytoplasmic accumulation of nuclear DNA. This causes the aberrant activation of cGAS-STING cytoplasmic DNA sensors, provoking SASP through induction of interferon-β. Notably, the blockage of this pathway prevents SASP in senescent hepatic stellate cells, accompanied by a decline of obesity-associated hepatocellular carcinoma development in mice. These findings provide valuable new insights into the roles and mechanisms of SASP and possibilities for their control.
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U2 - 10.1038/s41467-018-03555-8
DO - 10.1038/s41467-018-03555-8
M3 - Article
C2 - 29593264
AN - SCOPUS:85044524499
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1249
ER -