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PMID:21439629

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Citation

Zettl, M, Adrain, C, Strisovsky, K, Lastun, V and Freeman, M (2011) Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling. Cell 145:79-91

Abstract

Intramembrane proteolysis governs many cellular control processes, but little is known about how intramembrane proteases are regulated. iRhoms are a conserved subfamily of proteins related to rhomboid intramembrane serine proteases that lack key catalytic residues. We have used a combination of genetics and cell biology to determine that these "pseudoproteases" inhibit rhomboid-dependent signaling by the epidermal growth factor receptor pathway in Drosophila, thereby regulating sleep. iRhoms prevent the cleavage of potential rhomboid substrates by promoting their destabilization by endoplasmic reticulum (ER)-associated degradation; this mechanism has been conserved in mammalian cells. The exploitation of the intrinsic quality control machinery of the ER represents a new mode of regulation of intercellular signaling. Inactive cognates of enzymes are common, but their functions are mostly unclear; our data indicate that pseudoenzymes can readily evolve into regulatory proteins, suggesting that this may be a significant evolutionary mechanism.

Links

PubMed PMC3149277 Online version:10.1016/j.cell.2011.02.047

Keywords

Animals; Drosophila/cytology; Drosophila/metabolism; Drosophila Proteins/chemistry; Drosophila Proteins/metabolism; Endoplasmic Reticulum/metabolism; Evolution, Molecular; Membrane Proteins/chemistry; Peptide Hydrolases/genetics; Peptide Hydrolases/metabolism; Proteins/metabolism; Receptor, Epidermal Growth Factor/metabolism; Serine Endopeptidases; Signal Transduction

Significance

Annotations

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

MOUSE:RHBL2

enables

GO:0004252: serine-type endopeptidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:RHOM

involved_in

GO:0042058: regulation of epidermal growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

PROST:AARA

enables

GO:0008236: serine-type peptidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:RHDF1

involved_in

GO:0042059: negative regulation of epidermal growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:RHDF1

involved_in

GO:0010841: positive regulation of circadian sleep/wake cycle, wakefulness

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:RHDF1

NOT|enables

GO:0004252: serine-type endopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:RHDF1

located_in

GO:0005789: endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:RHDF1

involved_in

GO:0042059: negative regulation of epidermal growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0003731

P

Seeded From UniProt

complete

DROME:RHDF1

involved_in

GO:0042059: negative regulation of epidermal growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0014388

P

Seeded From UniProt

complete

DROME:RHDF1

involved_in

GO:0042059: negative regulation of epidermal growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0005672

P

Seeded From UniProt

complete

DROME:RHDF1

involved_in

GO:0042059: negative regulation of epidermal growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0004569

P

Seeded From UniProt

complete

DROME:RHDF1

located_in

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RHDF2

located_in

GO:0005789: endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:RHDF1

NOT|enables

GO:0004252: serine-type endopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:RHDF1

located_in

GO:0005789: endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:RHDF1

involved_in

GO:0050709: negative regulation of protein secretion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RHDF1

involved_in

GO:0061136: regulation of proteasomal protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RHDF2

NOT|enables

GO:0004252: serine-type endopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RHDF2

part_of

GO:0005789: endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RHDF2

involved_in

GO:0050709: negative regulation of protein secretion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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