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<p>Caspase-3 (CASP3) and caspase-7 (CASP7) are the two major executioner caspases that are proteolytically activated by upstream initiator caspases. They possess almost indistinguishable activity, which has led to the overall view that these caspases have functionally redundant roles. Here, we generate knock-in mice expressing cleavage-resistant CASP3(D175A) or CASP7(D198A). Our results show that proteolytic activation of CASP3 and CASP7 is decisive for their activity in vivo and controls redundant processes during embryonic development as combined expression of both CASP3(D175A) and CASP7(D198A) causes embryonic lethality. In adult mice, however, activation of CASP3 and CASP7 controls different processes in different tissues, without the involvement of apoptosis. While CASP7 activation is required for male fertility by controlling spermatogenesis, CASP3 activation appears crucial for lymphoid tissue development by regulating interferon signalling. Our findings shed light on emerging roles of caspases in non-apoptotic processes and provide impetus for reconsidering their involvement in physiological and pathological conditions.</p>

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Proteolytic activation of executioner caspase-3 and -7 regulates different physiological processes in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Noëlle Sieg,
  • Johanna Stachelscheid,
  • Besarta Thaqi,
  • Tanja Schwab,
  • Fabian Schorn,
  • Daniela Hahn,
  • Adrian Georg Simon,
  • Yuri Tolkach,
  • Nima Abedpour,
  • Simon E Tröder,
  • Ingo Voigt,
  • Felix Gaedke,
  • Katja Wiegmann,
  • Susanne Brodesser,
  • Astrid Schauss,
  • Branko Zevnik,
  • Martin Krönke,
  • Reinhard Büttner,
  • Alexander Quaas,
  • Michael Hallek,
  • Melanie Fritsch,
  • Hamid Kashkar

摘要

Caspase-3 (CASP3) and caspase-7 (CASP7) are the two major executioner caspases that are proteolytically activated by upstream initiator caspases. They possess almost indistinguishable activity, which has led to the overall view that these caspases have functionally redundant roles. Here, we generate knock-in mice expressing cleavage-resistant CASP3(D175A) or CASP7(D198A). Our results show that proteolytic activation of CASP3 and CASP7 is decisive for their activity in vivo and controls redundant processes during embryonic development as combined expression of both CASP3(D175A) and CASP7(D198A) causes embryonic lethality. In adult mice, however, activation of CASP3 and CASP7 controls different processes in different tissues, without the involvement of apoptosis. While CASP7 activation is required for male fertility by controlling spermatogenesis, CASP3 activation appears crucial for lymphoid tissue development by regulating interferon signalling. Our findings shed light on emerging roles of caspases in non-apoptotic processes and provide impetus for reconsidering their involvement in physiological and pathological conditions.