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PMID:21962518

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Citation

Liu, J, Xia, H, Kim, M, Xu, L, Li, Y, Zhang, L, Cai, Y, Norberg, HV, Zhang, T, Furuya, T, Jin, M, Zhu, Z, Wang, H, Yu, J, Li, Y, Hao, Y, Choi, A, Ke, H, Ma, D and Yuan, J (2011) Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 147:223-34

Abstract

Autophagy is an important intracellular catabolic mechanism that mediates the degradation of cytoplasmic proteins and organelles. We report a potent small molecule inhibitor of autophagy named "spautin-1" for specific and potent autophagy inhibitor-1. Spautin-1 promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two ubiquitin-specific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes. Beclin1 is a tumor suppressor and frequently monoallelically lost in human cancers. Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. Since USP10 mediates the deubiquitination of p53, regulating deubiquitination activity of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. Our study provides a molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1, and a potent small molecule inhibitor of autophagy as a possible lead compound for developing anticancer drugs.

Links

PubMed PMC3441147 Online version:10.1016/j.cell.2011.08.037

Keywords

Animals; Apoptosis Regulatory Proteins/metabolism; Autophagy; Class III Phosphatidylinositol 3-Kinases/metabolism; Endopeptidases/metabolism; Humans; Mice; Tumor Suppressor Protein p53/metabolism; Ubiquitin Thiolesterase/metabolism; Ubiquitination

Significance

Annotations

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

HUMAN:BECN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14694

F

Seeded From UniProt

complete

HUMAN:BECN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92995

F

Seeded From UniProt

complete

HUMAN:UBP10

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14457

F

Seeded From UniProt

complete

HUMAN:UBP10

involved_in

GO:0010506: regulation of autophagy

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBP10

enables

GO:0004843: thiol-dependent deubiquitinase

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:UBP10

enables

GO:0004197: cysteine-type endopeptidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:UBP13

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14457

F

Seeded From UniProt

complete

HUMAN:UBP13

involved_in

GO:0010506: regulation of autophagy

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBP13

enables

GO:0004843: thiol-dependent deubiquitinase

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

See also

References

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