Alternative cell death mechanisms in development and beyond

Abstract

A canonical regulatory pathway involving the members of the Bcl-2 and caspase families has been established to regulate developmental apoptosis in nematodes and flies. However, mutant mice that have major deficiencies in this apoptosis pathway show only relatively minor developmental defects. Recent revelations indicate that multiple mechanisms are involved in regulating cell death during mammalian development, tissue homeostasis, and pathological cell loss. Here, we critically evaluate the evidence demonstrating the existence of alternative cell death mechanisms, including apoptosis of lower organisms in the absence of canonical apoptosis mediators, autophagic cell death, necroptosis, elimination by shedding, keratinocyte death by cornification, and cell-cell cannibalism by entosis. The physiological relevance of alternative cell death mechanisms as primary and backup mechanisms is discussed.

Figure 1.

The signaling complexes are induced by TNFα to mediate NF-κB activation, apoptosis, and necroptosis. Stimulation of TNFR1 by TNFα leads to the formation of an intracellular complex at the cytoplasmic membrane (complex I) that includes TRADD, TRAF2, RIP1, and cIAP1. Ubiquitination of RIP1 at K377 by cIAP1 leads to the recruitment of NEMO, a regulatory subunit of the IKK complex that in turn activates the NF-κB pathway. RIP1 is also involved in the formation of complex IIa, including FADD and caspase-8, to activate a caspase cascade to mediate apoptosis. Under apoptosis-deficient conditions, or when cells are infected by certain viruses, RIP1 interacts with RIP3 to form complex IIb, which is involved in mediating necroptosis. The formation complex IIb requires the kinase activity of RIP1 that is inhibited by Nec-1. (Reproduced from Christofferson and Yuan [2009] with permission from Elsevier [© 2009].)

Figure 2.

Types of cell death seen in small intestine. (Reproduced with permission from Mayhew et al. [1999].) In type 1 cell death, a sequence of changes (1–4) leads to complete cells being extruded into the lumen. In type 2 cell death, only anucleate apical cell fragments are extruded. Two variants are distinguishable by the fate of the nucleated basal cell fragments. Type 2a cell death (sequence 1–3) creates large intercellular spaces extending from the apical fragment to the basal lamina and containing debris for phagocytosis. Type 2b cell death involves cell shrinkage and in situ degeneration of nucleated fragments in narrow intercellular spaces between adjacent enterocytes (sequence 1–4). The type 1 and type 2 cell deaths exhibit features of apoptosis. Type 3 cell death is reminiscent of necrosis. Cell swelling (1) and degradation (2–4) lead to breaks in epithelial continuity (open arrows), and end in spillage of degraded cell remnants into the lumen (2) or subtotal degradation and extrusion of a complete cell remnant (3–4). (LPM) Lamina propria macrophages; (IEL) intraepithelium lymphocytes.

Figure 3.

An illustration of entosis. A matrix-detached target cell (top left, blue) invades (arrow) into a neighboring host cell (turquoise) by a Rho-dependent contractile actomyosin force-based mechanism, requiring E-cadherin and adherens junction formation (blue junction at the cell–cell interface). The target cell is then internalized by the host. An internalized cell can be degraded by lysosomal enzymes (the red cell), can undergo cell division inside the host, or an be released from the host. (Kindly contributed by Michael Overholtzer and Joan S. Brugge.)