Core programmed cell death machinery in Caenorhabditis elegans

Most somatic and germline apoptotic deaths in Caenorhabditis elegans are initiated by four proteins acting in a linear pathway. In living cells the BCL2-family protein CED-9 sits on mitochondria and binds an asymmetric dimer of the Apaf-1-like adaptor CED-4, holding it in an inactive state. A death signal raises the level of the BH3-only protein EGL-1, whose BH3 helix binds a hydrophobic groove on CED-9 and remodels it so that the CED-4 dimer is released. Free CED-4 dimers assemble into an ATP-bound octameric apoptosome that relocates to the nuclear periphery, recruits two molecules of the CED-3 caspase zymogen into its central hutch and drives their autocatalytic maturation. Active CED-3 then cleaves execution substrates such as DCR-1 and CED-8, which promote chromosome fragmentation and phosphatidylserine exposure for corpse engulfment. In the adult germline, DNA damage feeds into the same machinery through the p53-family transcription factor CEP-1, which induces transcription of egl-1 and of a second BH3-only gene, ced-13. CED-13 can also bind CED-9 and release CED-4, but its loss has only a small effect on DNA damage-induced germline death, so EGL-1 remains the main trigger on that route as well. Unlike the mammalian intrinsic pathway, the worm pathway has no known requirement for mitochondrial outer membrane permeabilization or cytochrome c release; CED-9 inhibits by direct sequestration of CED-4 rather than by controlling a pore.

Boundary. This is a concrete C. elegans module for the decision and activation steps of apoptosis: BH3-only trigger, BCL2-family restraint, adaptor oligomerization and caspase activation, plus caspase cleavage of execution substrates as the module output. Corpse recognition and engulfment are a separate module (MODULE:phagocytic_engulfment); CED-3 cleavage of CED-8 is the hand-off point, since acCED-8 promotes phosphatidylserine exposure that engulfing cells recognize. CEP-1 is modeled as an optional upstream part because it is needed only for DNA damage-induced germline death. Developmental transcriptional control of egl-1 (for example TRA-1 in the HSN neurons, or CES-1/CES-2 in the NSM sister cells) is cell-type specific upstream regulation and is not modeled here. Systemic inputs. Germline DNA-damage apoptosis is also modulated from outside the germ cell. The intestinal PMK-1/p38 target SYSM-1 (gene review genes/worm/sysm-1, UniProtKB:Q22714) is a secreted ShKT-domain protein that reaches the germline and is required for full DNA damage-induced germ cell apoptosis. It acts in parallel to or downstream of CEP-1, since egl-1 and ced-13 are still induced in pmk-1 mutants (PMID:35121747). Its molecular activity is unknown, so it is recorded here as a systemic modulator and not modeled as a part of the core machinery. Relation to the mammalian modules. MODULE:bcl2_family_momp_control and MODULE:intrinsic_apoptotic_signaling describe BAX/BAK-mediated outer membrane permeabilization, cytochrome c release and the CYCS/APAF1/CASP9 apoptosome. None of those steps is part of this module. C. elegans has no BAX/BAK-type effector in the core pathway, and CED-4 oligomerizes without cytochrome c once CED-9 releases it. The ced-9 gene review removed BCL2-family PAINT transfers for cytochrome c release and channel activity on these grounds. Mitochondria matter here as the site where CED-9 holds CED-4, not as a source of released apoptogenic factors. CED-3 combines the initiator role of CASP9 and the executioner role of CASP3/CASP7 in the mammalian MODULE:apoptotic_execution_phase. Members and terms. All six members have completed gene reviews. EGL-1 has no fitting GO molecular function: GO:0051434 BH3 domain binding describes the groove-side receptor (CED-9), not the BH3 ligand. The EGL-1 annoton therefore uses the free-text proposed term "pro-survival BCL2 family protein inhibitor activity" from the egl-1 review, as in MODULE:bcl2_family_momp_control for the mammalian BH3-only sensitizers. CED-9 carries two activities, CED-4 sequestration (GO:0140311) and EGL-1 BH3 binding (GO:0051434), matching its two core functions. CED-13 is a second CEP-1-induced BH3-only protein that binds CED-9. Its gene review gives it the same proposed molecular function as EGL-1, and it is modeled as a second annoton in the optional CEP-1 DNA-damage part rather than in the main trigger step. The weighting is deliberate: ced-13 overexpression kills somatic cells and its BH3 peptide displaces CED-4 from CED-9, but loss of ced-13 has only limited effects, confined to DNA damage-induced germline apoptosis, so it is a minor and largely redundant trigger next to EGL-1. Two CED-13 roles outside this boundary are not modeled: physiological germline death in cisd mutants, which depends on CED-13 but not EGL-1 (PMID:29666474), and a non-apoptotic pro-longevity response to mitochondrial ROS that uses CED-13, CED-9, CED-4 and CED-3 but not EGL-1 (PMID:24813612). Non-core branches recorded in the gene reviews (local EGL-1/CED-9/CED-4/CED-3 activity in synapse pruning, CED-9 roles in mitochondrial dynamics, CED-3 cleavage of heterochronic regulators) are outside this boundary. No production GO-CAM in gocams/index.tsv contains these proteins.