RESUMEN
Multicellular organisms use programmed cell death to eliminate unwanted or potentially harmful cells. Improper cell corpse removal can lead to autoimmune diseases. The development of interventional therapies that increase engulfment activity could represent an attractive approach to treat such diseases. Here, we describe mtm-1, the Caenorhabditis elegans homolog of human myotubularin 1, as a potential negative regulator of apoptotic cell corpse clearance. Loss of mtm-1 function leads to substantially reduced numbers of persistent cell corpses in engulfment mutants, which is a result of a restoration of engulfment function rather than of impaired or delayed programmed cell death. Epistatic analyses place mtm-1 upstream of the ternary GEF complex, which consists of ced-2, ced-5 and ced-12, and parallel to mig-2. Over-activation of engulfment results in the removal of viable cells that have been brought to the verge of death under limiting caspase activity. In addition, mtm-1 also promotes phagosome maturation in the hermaphrodite gonad, potentially through CED-1 receptor recycling. Finally, we show that the CED-12 PH domain can bind to PtdIns(3,5)P(2) (one target of MTM-1 phosphatase activity), suggesting that MTM-1 might regulate CED-12 recruitment to the plasma membrane.
Asunto(s)
Apoptosis/fisiología , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/citología , Caenorhabditis elegans/metabolismo , Proteínas Portadoras/metabolismo , Proteínas del Citoesqueleto/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Animales , Animales Modificados Genéticamente , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis , Caenorhabditis elegans/genética , Caenorhabditis elegans/crecimiento & desarrollo , Proteínas de Caenorhabditis elegans/genética , Proteínas Portadoras/genética , Proteínas del Citoesqueleto/genética , Regulación del Desarrollo de la Expresión Génica , Genes de Helminto , Humanos , Proteínas de la Membrana/genética , Modelos Biológicos , Mutación , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/deficiencia , Proteínas Tirosina Fosfatasas no Receptoras/genética , Transducción de Señal , Proteínas de Unión al GTP rac/genética , Proteínas de Unión al GTP rac/metabolismoRESUMEN
The engulfment of apoptotic cell corpses is an evolutionary conserved process used by multicellular systems to remove cells with inappropriate potential (e.g., self-reactive T-cells, potentially cancerous cells). Neighboring or specialized phagocytic cells remove cell corpses through distinct steps: they first recognize the cell on the verge of death, then reorchestrate their cellular architecture toward it, actively contribute to cell killing, and eventually engulf the corpse. Thus engulfment signaling must be tightly controlled to maintain tissue homeostasis. Signaling cascades mediating cell corpse clearance likely converge at the level of the small GTPase CED-10 (Rac1); given this key position, CED-10 must be subject to a tight regulatory mechanism to prevent inappropriate phagocytic events. Here, we discuss recent work characterizing srgp-1 (nematode ortholog of mammalian srGAP), a candidate GTPase activating protein (GAP) for CED-10 involved in cell corpse clearance and "sick" cell killing in C. elegans. We additionally discuss several possible determinants of SRGP-1 function, contributing to either SRGP-1 localization and/or activation. We also survey other potential candidate GTPases that might contribute to cell corpse clearance in C. elegans, and eventually recapitulate the role of engulfment during cell killing.