Caspase-Mediated Apoptotic Mechanisms in Cellular Stress Responses

Apoptosis, or programmed cell death, is essential for development, tissue homeostasis and the response to diverse cellular stresses. Central to this process are caspases, a family of cysteine proteases that orchestrate the dismantling of cells through proteolytic cascades. Initiator caspases such as caspase-2, ‑8 and ‑9 respond to distinct stress signals via multiprotein platforms: the apoptosome assembles in response to mitochondrial cytochrome c release following DNA damage or other intrinsic insults, while the PIDDosome engages caspase-2 in the face of genotoxic stress. In parallel, death receptor activation triggers caspase-8 recruitment to the DISC (death-inducing signalling complex) in the extrinsic pathway. Once engaged, initiator caspases cleave and activate executioner caspases (notably caspase-3 and ‑7), which orchestrate morphological changes including nuclear condensation, membrane blebbing and formation of apoptotic bodies. Crosstalk between these pathways is mediated by BH3-only proteins such as BID, which connect caspase-8 activation to mitochondrial outer membrane permeabilisation. Emerging evidence expands the role of caspases beyond canonical apoptosis to stress-related contexts including oxidative insults, endoplasmic reticulum stress and pathogen infection, where they modulate alternative cell death programmes and inflammatory responses. Dysregulation of caspase activation underpins a spectrum of diseases, from neurodegeneration to cancer, highlighting their potential as therapeutic targets in conditions characterised by aberrant cell survival or loss.

Research from Nature Portfolio

New investigations have revealed that initiator caspases translocate dynamically between cytoplasm and nucleus during apoptotic induction, where they may directly cleave nuclear substrates to promote chromatin condensation and DNA fragmentation in response to chemotherapeutic stress. Complementary studies have uncovered a non-apoptotic function of caspase-2 in neuronal synaptic plasticity; by targeting a key component of the mTORC2–Akt–GSK3β axis, caspase-2 regulates AMPA receptor endocytosis, thereby influencing cognitive flexibility and behavioural adaptation under physiological stress conditions. These findings underscore the multifaceted roles of caspases in both executing cell death and modulating cellular responses to environmental cues.

Caspase-Mediated Apoptotic Mechanisms in Cellular Stress Responses publication trend

The graph below shows the total number of articles in caspase-mediated apoptotic mechanisms in cellular stress responses across all publications each year (not limited to Nature Index journals).

Technical terms

Apoptosis: Programmed cell death characterised by orderly cellular disassembly and minimal inflammation.

Caspase: Family of cysteine proteases involved in initiation and execution of apoptotic and other cell death pathways.

Initiator caspase: Caspase activated by oligomerisation platforms (e.g. caspase-2, ‑8, ‑9) that triggers downstream cascades.

Executioner caspase: Effector caspase (e.g. caspase-3, ‑7) that cleaves cellular substrates to effect apoptosis.

Apoptosome: Multimeric complex that recruits and activates caspase-9 upon cytochrome c release from mitochondria.

PIDDosome: Multiprotein assembly that facilitates caspase-2 activation in response to DNA damage.

Ferroptosis: Iron-dependent form of regulated cell death driven by lipid peroxidation.

ER stress: Cellular stress arising from accumulation of misfolded proteins in the endoplasmic reticulum triggering unfolded protein responses.

GSDME (Gasdermin E): Pore-forming protein cleaved by caspases to mediate membrane permeabilisation and inflammatory cell death.

BID: BH3-only pro-apoptotic Bcl-2 family member that links extrinsic caspase activation to mitochondrial outer membrane permeabilisation.

References

1. Caspase-2 protects against ferroptotic cell death. Cell Death & Disease (2024).
2. Dissecting caspase-2-mediated cell death: from intrinsic PIDDosome activation to chemical modulation. Protein & Cell (2024).
3. ER stress induces caspase‐2‐tBID‐GSDME‐dependent cell death in neurons lytically infected with herpes simplex virus type 2. The EMBO Journal (2023).
4. Apoptosis regulation by subcellular relocation of caspases. Scientific Reports (2018).
5. Caspase-2 promotes AMPA receptor internalization and cognitive flexibility via mTORC2-AKT-GSK3β signaling. Nature Communications (2019).