title: Destruction of DDIT3/CHOP protein by wild-type SPOP but not prostate cancer-associated mutants.
abstract: Characterization of the exome and genome of prostate cancers by next-generation sequencing has identified numerous genetic alternations. SPOP (speckle-type POZ protein) was identified as one of the most frequently affected genes by somatic point mutations in prostate cancer, suggesting SPOP is potentially a key driver for prostate cancer development and progression. However, how SPOP mutations contribute to prostate cancer remains to be elucidated. SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex and selectively recruits substrates for their ubiquitination and subsequent degradation. DDIT3 is an endoplasmic reticulum (ER) stress-responsive transcription factor playing an essential role in apoptotic execution pathways triggered by ER stress. Here, we identified DDIT3/CHOP as a bona fide substrate for the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP recognizes a Ser/Thr-rich degron in the transactivation domain of DDIT3 and triggers DDIT3 degradation via the ubiquitin-proteasome pathway. Strikingly, prostate cancer-associated mutants of SPOP are defective in promoting DDIT3 degradation. This study reveals novel molecular events underlying the regulation of DDIT3 protein homeostasis and provides insight in understanding the relationship between SPOP mutations and ER stress dysregulation in prostate cancer.
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200433, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, P. R. China.
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Zhang
authors.forename: Kun
authors.initials: K
authors.lastname: Gao
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Jin
authors.forename: Jian
authors.initials: J
authors.lastname: An
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Yu
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dejie
authors.initials: D
authors.lastname: Wang
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.forename: Long
authors.initials: L
authors.lastname: Yu
authors.forename: Chenji
authors.initials: C
authors.lastname: Wang
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D008297:Male; D046912:Multiprotein Complexes; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics*; D051742:Transcription Factor CHOP / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D054875:Ubiquitination
chemical_list: C503645:CUL3 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; C479529:RBX1 protein, human; D012097:Repressor Proteins; C509761:SPOP protein, human; D051742:Transcription Factor CHOP
keywords: DDIT3; SPOP; endoplasmic reticulum stress; prostate cancer; proteasomal degradation