Distinct cathepsins control necrotic cell death mediated by pyroptosis inducers and lysosome-destabilizing agents

Jürgen Brojatsch, Heriberto Lima, Deborah Palliser, Lee S. Jacobson, Stefan M. Muehlbauer, Raquel Furtado, David L. Goldman, Michael P. Lisanti, Kartik Chandran

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Necrotic cell death triggers a range of biological responses including a strong adaptive immune response, yet we know little about the cellular pathways that control necrotic cell death. Inhibitor studies suggest that proteases, and in particular cathepsins, drive necrotic cell death. The cathepsin B-selective inhibitor CA-074-Me blocks all forms of programmed necrosis by an unknown mechanism. We found that cathepsin B deficiency does not prevent induction of pyroptosis and lysosome-mediated necrosis suggesting that CA-074-Me blocks necrotic cell death by targeting cathepsins other than cathepsin B. A single cathepsin, cathepsin C, drives necrotic cell death mediated by the lysosomedestabilizing agent Leu-Leu-OMe (LLOMe). Here we present evidence that cathepsin C-deficiency and CA-074-Me block LLOMe killing in a distinct and cell type-specific fashion. Cathepsin Cdeficiency and CA-074-Me block LLOMe killing of all myeloid cells, except for neutrophils. Cathepsin C-deficiency, but not CA-074-Me, blocks LLOMe killing of neutrophils suggesting that CA-074-Me does not target cathepsin C directly, consistent with inhibitor studies using recombinant cathepsin C. Unlike other cathepsins, cathepsin C lacks endoproteolytic activity, and requires activation by other lysosomal proteases, such as cathepsin D. Consistent with this theory, we found that lysosomotropic agents and cathepsin D downregulation by siRNA block LLOMe-mediated necrosis. Our findings indicate that a proteolytic cascade, involving cathepsins C and D, controls LLOMe-mediated necrosis. In contrast, cathepsins C and D were not required for pyroptotic cell death suggesting that distinct cathepsins control pyroptosis and lysosome-mediated necrosis.

Original languageEnglish (US)
Pages (from-to)964-972
Number of pages9
JournalCell Cycle
Volume14
Issue number7
DOIs
StatePublished - Apr 1 2015

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Keywords

  • Caspase-1
  • IL
  • Inflammasome
  • Interleukin
  • L-leucyl-L-leucine methyl ester
  • LMN
  • LPS
  • Lipopolysaccharide
  • Lysosome rupture
  • Lysosome-mediated necrosis
  • NLR
  • Necrosis
  • Nucleotidebinding domain and leucine rich repeat
  • Pyroptosis abbreviations: LLOMe

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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