2. Academic Validation
  3. Dissecting caspase-2-mediated cell death: from intrinsic PIDDosome activation to chemical modulation

Dissecting caspase-2-mediated cell death: from intrinsic PIDDosome activation to chemical modulation

  • Protein Cell. 2024 Apr 27:pwae020. doi: 10.1093/procel/pwae020.
Mengxue Zeng 1 2,  Kun Wang 2,  Qingcui Wu 2,  Jingjin Ding 2 3 4,  Dan Xie 1,  Xiangbing Qi 2,  Feng Shao 1 2 3 5 6 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 2 National Institute of Biological Sciences, Beijing, Beijing 102206, P. R. China.
  • 3 Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 Research Unit of Pyroptosis and Immunity, Chinese Academy of Medical Sciences and National Institute of Biological Sciences, Beijing, Beijing 102206, China.
  • 6 Changping Laboratory, Beijing 102206, China.
  • 7 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China.
  • 8 New Cornerstone Science Laboratory, Shenzhen 518000, China.
PMID: 38676703 DOI: 10.1093/procel/pwae020
Abstract

Caspase-2, a highly conserved member of the Caspase family, is considered an initiator Caspase that triggers Apoptosis in response to some cellular stresses. Previous studies suggest that an intracellular multi-protein complex PIDDosome, induced by genotoxic stress, serves as a platform for caspase-2 activation. However, due to caspase-2's inability to process effector caspases, the mechanism underlying caspase-2-mediated cell death upon PIDDosome activation remains unclear. Here we conducted an unbiased genome-wide genetic screen and identified that the Bcl2 family protein BID is required for PIDDosome-induced, caspase-2-mediated Apoptosis. PIDDosome-activated caspase-2 directly and functionally processes BID to signal the mitochondrial pathway for Apoptosis induction. Additionally, a designed chemical screen identified a compound, HUHS015, that specifically activates caspase-2-mediated Apoptosis. HUHS015-stimulated Apoptosis also requires BID but is independent of the PIDDosome. Through extensive structure-activity relationship efforts, we identified a derivative with a potency of ~ 60 nmol/L in activating caspase-2-mediated Apoptosis. The HUHS015-series of compounds act as efficient agonists that directly target the interdomain linker in caspase-2, representing a new mode of initiator Caspase activation. Human and mouse caspase-2 differ in two crucial residues in the linker, rendering a selectivity of the agonists for human caspase-2. The caspase-2 agonists are valuable tools to explore the physiological roles of caspase-2-mediated cell death and a base for developing small-molecule drugs for relevant diseases.

Keywords

BID; PIDDosome; agonist; apoptosis; caspase-2; chemical screen.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z