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PMID:21490059

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Citation

Neukomm, LJ, Nicot, AS, Kinchen, JM, Almendinger, J, Pinto, SM, Zeng, S, Doukoumetzidis, K, Tronchère, H, Payrastre, B, Laporte, JF and Hengartner, MO (2011) The phosphoinositide phosphatase MTM-1 regulates apoptotic cell corpse clearance through CED-5-CED-12 in C. elegans. Development 138:2003-14

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.

Links

PubMed Online version:10.1242/dev.060012

Keywords

Animals; Animals, Genetically Modified; Apoptosis/genetics; Apoptosis/physiology; Caenorhabditis elegans/cytology; Caenorhabditis elegans/genetics; Caenorhabditis elegans/growth & development; Caenorhabditis elegans/metabolism; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/metabolism; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cytoskeletal Proteins/genetics; Cytoskeletal Proteins/metabolism; Gene Expression Regulation, Developmental; Genes, Helminth; Humans; Membrane Proteins/genetics; Membrane Proteins/metabolism; Models, Biological; Mutation; Phosphoproteins/genetics; Phosphoproteins/metabolism; Protein Tyrosine Phosphatases, Non-Receptor/deficiency; Protein Tyrosine Phosphatases, Non-Receptor/genetics; Protein Tyrosine Phosphatases, Non-Receptor/metabolism; Signal Transduction; rac GTP-Binding Proteins/genetics; rac GTP-Binding Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:CED12

enables

GO:0005547: phosphatidylinositol-3,4,5-trisphosphate binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:CED12

enables

GO:0070273: phosphatidylinositol-4-phosphate binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:CED12

enables

GO:0080025: phosphatidylinositol-3,5-bisphosphate binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:MTMR1

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:MTMR1

enables

GO:0004438: phosphatidylinositol-3-phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:MTMR1

located_in

GO:0005938: cell cortex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:MTMR1

located_in

GO:0045179: apical cortex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:MTMR1

involved_in

GO:0046839: phospholipid dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:MTMR1

enables

GO:0052629: phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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