Lysoptosis is an evolutionarily conserved cell death pathway moderated by intracellular serpins

• Published in: Communications biology Vol. 5; no. 1; pp. 47 - 25
• Main Authors: Luke, Cliff J., Markovina, Stephanie, Good, Misty, Wight, Ira E., Thomas, Brian J., Linneman, John M., Lanik, Wyatt E., Koroleva, Olga, Coffman, Maggie R., Miedel, Mark T., Gong, Qingqing, Andress, Arlise, Campos Guerrero, Marlene, Wang, Songyan, Chen, LiYun, Beatty, Wandy L., Hausmann, Kelsey N., White, Frances V., Fitzpatrick, James A. J., Orvedahl, Anthony, Pak, Stephen C., Silverman, Gary A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-01-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/31; 14; 14/19; 14/28; 14/34; 14/63; 38; 631/80/474; 631/80/642/1624; 631/80/82; Animals; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Apoptosis; Biology; Biomedical and Life Sciences; Cathepsin L; Cathepsins; Cell Death; Cell Line, Tumor; Cysteine proteinase; Epithelial cells; Epithelial Cells - physiology; Humans; Life Sciences; Mice; Phenotypes; Proteolysis; Serine proteinase inhibitors; Serpins - genetics; Serpins - metabolism
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02953-x

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.
Cliff Luke et al. report that lysoptosis is a eukaryotic stand-alone regulated cell death pathway. They identify that this new cell death modality predominates in the absence of neutralizing endogenous inhibitors.