期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：50
页码：15372-15377
DOI：10.1073/pnas.1522006112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMany short-lived proteins perform important cellular functions that must be tightly regulated. EID1 is an unstable protein implicated in the control of transcription, differentiation, and genomic integrity. EID1 is particularly unstable in G0 cells. Here we show that an SCF complex containing the orphan F-box only protein FBXO21 is the ubiquitin ligase that recognizes EID1 in both cycling and G0 cells and that it recognizes a modular, peptidic domain within EID1. This degron overlaps with the EID1 region that binds to the retinoblastoma tumor suppressor protein (pRB) and to melanoma-associated antigen (MAGE) proteins, suggesting that multiple proteins compete for binding to EID1 and secondarily influence its ubiquitinylation. This study sheds light on the regulation of EID1, the function of FBXO21, and control of protein turnover by ubiquitin ligases. EP300-interacting inhibitor of differentiation 1 (EID1) belongs to a protein family implicated in the control of transcription, differentiation, DNA repair, and chromosomal maintenance. EID1 has a very short half-life, especially in G0 cells. We discovered that EID1 contains a peptidic, modular degron that is necessary and sufficient for its polyubiquitylation and proteasomal degradation. We found that this degron is recognized by an Skp1, Cullin, and F-box (SCF)-containing ubiquitin ligase complex that uses the F-box Only Protein 21 (FBXO21) as its substrate recognition subunit. SCFFBXO21 polyubiquitylates EID1 both in vitro and in vivo and is required for the efficient degradation of EID1 in both cycling and quiescent cells. The EID1 degron partially overlaps with its retinoblastoma tumor suppressor protein-binding domain and is congruent with a previously defined melanoma-associated antigen-binding motif shared by EID family members, suggesting that binding to retinoblastoma tumor suppressor and melanoma-associated antigen family proteins could affect the polyubiquitylation and turnover of EID family members in cells.
