TY - JOUR
T1 - Lysoptosis is an evolutionarily conserved cell death pathway moderated by intracellular serpins
AU - Luke, Cliff J.
AU - Markovina, Stephanie
AU - Good, Misty
AU - Wight, Ira E.
AU - Thomas, Brian J.
AU - Linneman, John M.
AU - Lanik, Wyatt E.
AU - Koroleva, Olga
AU - Coffman, Maggie R.
AU - Miedel, Mark T.
AU - Gong, Qingqing
AU - Andress, Arlise
AU - Campos Guerrero, Marlene
AU - Wang, Songyan
AU - Chen, Li Yun
AU - Beatty, Wandy L.
AU - Hausmann, Kelsey N.
AU - White, Frances V.
AU - Fitzpatrick, James A.J.
AU - Orvedahl, Anthony
AU - Pak, Stephen C.
AU - Silverman, Gary A.
N1 - Funding Information:
This work was supported by NIH grants R01DK104946 (G.A.S.), R01DK114047 (C.J.L. and G.A.S), R01DK118568 (M.G.), K08CA237822 (S.M.), K08AI144033 (A.O.), The Society for Pediatric Research Physician Scientist Award (A.O.), American Society for Clinical Oncology (ASCO) Career Development Award (S.M.), The Children’s Discovery Institute of St. Louis Children’s Hospital Foundation (C.J.L., S.C.P., and M.G). J.A.J.F is supported by the Chan Zuckerberg Initiative as an Imaging Scientist (2020-225726). Washington University Center for Cellular Imaging (WUCCI) is supported by Washington University School of Medicine, The Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), and the Foundation for Barnes-Jewish Hospital (3770). We would like to thank Dr’s Ekkehard Weber, Martin Luther University, Germany and Stuart Kornfeld, Washington University in St. Louis, School of Medicine, USA for the kind gifts of CTSB and -D antibodies, respectively.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Lysosomal membrane permeabilization (LMP) and cathepsin release typifies lysosome-dependent cell death (LDCD). However, LMP occurs in most regulated cell death programs suggesting LDCD is not an independent cell death pathway, but is conscripted to facilitate the final cellular demise by other cell death routines. Previously, we demonstrated that Caenorhabditis elegans (C. elegans) null for a cysteine protease inhibitor, srp-6, undergo a specific LDCD pathway characterized by LMP and cathepsin-dependent cytoplasmic proteolysis. We designated this cell death routine, lysoptosis, to distinguish it from other pathways employing LMP. In this study, mouse and human epithelial cells lacking srp-6 homologues, mSerpinb3a and SERPINB3, respectively, demonstrated a lysoptosis phenotype distinct from other cell death pathways. Like in C. elegans, this pathway depended on LMP and released cathepsins, predominantly cathepsin L. These studies suggested that lysoptosis is an evolutionarily-conserved eukaryotic LDCD that predominates in the absence of neutralizing endogenous inhibitors.
AB - Lysosomal membrane permeabilization (LMP) and cathepsin release typifies lysosome-dependent cell death (LDCD). However, LMP occurs in most regulated cell death programs suggesting LDCD is not an independent cell death pathway, but is conscripted to facilitate the final cellular demise by other cell death routines. Previously, we demonstrated that Caenorhabditis elegans (C. elegans) null for a cysteine protease inhibitor, srp-6, undergo a specific LDCD pathway characterized by LMP and cathepsin-dependent cytoplasmic proteolysis. We designated this cell death routine, lysoptosis, to distinguish it from other pathways employing LMP. In this study, mouse and human epithelial cells lacking srp-6 homologues, mSerpinb3a and SERPINB3, respectively, demonstrated a lysoptosis phenotype distinct from other cell death pathways. Like in C. elegans, this pathway depended on LMP and released cathepsins, predominantly cathepsin L. These studies suggested that lysoptosis is an evolutionarily-conserved eukaryotic LDCD that predominates in the absence of neutralizing endogenous inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=85122805400&partnerID=8YFLogxK
U2 - 10.1038/s42003-021-02953-x
DO - 10.1038/s42003-021-02953-x
M3 - Article
C2 - 35022507
AN - SCOPUS:85122805400
SN - 2399-3642
VL - 5
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 47
ER -