TY - JOUR
T1 - Nuclear-accumulated SQSTM1/p62-based ALIS act as microdomains sensing cellular stresses and triggering oxidative stress-induced parthanatos
AU - Noguchi, Takuya
AU - Suzuki, Midori
AU - Mutoh, Natsumi
AU - Hirata, Yusuke
AU - Tsuchida, Mei
AU - Miyagawa, Sayoko
AU - Hwang, Gi Wook
AU - Aoki, Junken
AU - Matsuzawa, Atsushi
N1 - Funding Information:
We thank all members of Lab of Health Chemistry for helpful discussions. This work was supported by Grant-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS) and the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT), including KAKENHI on Innovative Areas “Oxygen Biology: a new criterion for integrated understanding of life” (No. 17H05518) of MEXT and KAKENHI on Innovative Areas “New aspect of the ubiquitin system: its enormous roles in protein regulation” (No. 15H01168) of MEXT, the Mitsubishi Foundation, the Shimabara Science Promotion Foundation, the Japan Foundation of Applied Enzymology, the Life Science Foundation of Japan, the Fugaku Trust for Medicinal Research, and the Takeda Science Foundation.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Aggresome-like induced structures (ALIS) have been described as ubiquitinated protein-containing aggresomes transiently formed in response to various stresses. In this study, we provide evidence that ALIS composed of SQSTM1/p62 act as a key determinant of oxidative stress-induced parthanatos, which is newly discovered and distinct from regular programmed cell death. Interestingly, we first found that chemical stresses induced by particular chemical drugs, such as several cephalosporin antibiotics, cause oxidative stress-mediated parthanatos, accompanied by the ALIS formation. Blocking the ALIS formation potently suppressed the parthanatos, and p62 knockout cells exhibited the attenuated ALIS formation and high resistance to parthanatos. Moreover, we also found that the redox-sensing activity of p62 is required for nuclear accumulation of the p62-based ALIS, resulting in the induction of parthanatos. Together, our results demonstrate unexpected functions of p62 and ALIS as cell death mediators sensing oxidative stress, and thus uncover a novel mechanism whereby p62 mediates parthanatos.
AB - Aggresome-like induced structures (ALIS) have been described as ubiquitinated protein-containing aggresomes transiently formed in response to various stresses. In this study, we provide evidence that ALIS composed of SQSTM1/p62 act as a key determinant of oxidative stress-induced parthanatos, which is newly discovered and distinct from regular programmed cell death. Interestingly, we first found that chemical stresses induced by particular chemical drugs, such as several cephalosporin antibiotics, cause oxidative stress-mediated parthanatos, accompanied by the ALIS formation. Blocking the ALIS formation potently suppressed the parthanatos, and p62 knockout cells exhibited the attenuated ALIS formation and high resistance to parthanatos. Moreover, we also found that the redox-sensing activity of p62 is required for nuclear accumulation of the p62-based ALIS, resulting in the induction of parthanatos. Together, our results demonstrate unexpected functions of p62 and ALIS as cell death mediators sensing oxidative stress, and thus uncover a novel mechanism whereby p62 mediates parthanatos.
UR - http://www.scopus.com/inward/record.url?scp=85058612505&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058612505&partnerID=8YFLogxK
U2 - 10.1038/s41419-018-1245-y
DO - 10.1038/s41419-018-1245-y
M3 - Article
C2 - 30546061
AN - SCOPUS:85058612505
VL - 9
JO - Cell Death and Disease
JF - Cell Death and Disease
SN - 2041-4889
IS - 12
M1 - 1193
ER -
