title: The phosphoinositide phosphatase MTM-1 regulates apoptotic cell corpse clearance through CED-5-CED-12 in C. elegans.
abstract: 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.
authors.affiliation: Institute of Molecular Life Science, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Lukas Jakob
authors.initials: LJ
authors.lastname: Neukomm
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Nicot
authors.forename: Jason Michael
authors.initials: JM
authors.lastname: Kinchen
authors.forename: Johann
authors.initials: J
authors.lastname: Almendinger
authors.forename: Sérgio Morgado
authors.initials: SM
authors.lastname: Pinto
authors.forename: Sheng
authors.initials: S
authors.lastname: Zeng
authors.forename: Kimon
authors.initials: K
authors.lastname: Doukoumetzidis
authors.forename: Hélène
authors.initials: H
authors.lastname: Tronchère
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
authors.forename: Jocelyn Franck
authors.initials: JF
authors.lastname: Laporte
authors.forename: Michael Otmar
authors.initials: MO
authors.lastname: Hengartner
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D017238:Genes, Helminth; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438369:CED-12 protein, C elegans; C479695:CED-2 protein, C elegans; C111579:CED-5 protein, C elegans; C112888:CED-6 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin; C442327:Mig-2 protein, C elegans; D020744:rac GTP-Binding Proteins