Poly(A) binding protein (PABP) homeostasis is mediated by the stability of its inhibitor, Paip2.
The poly(A)-binding protein (PABP) is a unique translation initiation factor in that it binds to the mRNA 3' poly(A) tail and stimulates recruitment of the ribosome to the mRNA at the 5' end. PABP activity is tightly controlled by the PABP-interacting protein 2 (Paip2), which inhibits translation by displacing PABP from the mRNA. Here, we describe a close interplay between PABP and Paip2 protein levels in the cell. We demonstrate a mechanism for this co-regulation that involves an E3 ubiquitin ligase, EDD, which targets Paip2 for degradation. PABP depletion by RNA interference (RNAi) causes co-depletion of Paip2 protein without affecting Paip2 mRNA levels. Upon PABP knockdown, Paip2 interacts with EDD, which leads to Paip2 ubiquitination. Supporting a critical role for EDD in Paip2 degradation, knockdown of EDD expression by siRNA leads to an increase in Paip2 protein stability. Thus, we demonstrate that the turnover of Paip2 in the cell is mediated by EDD and is regulated by PABP. This mechanism serves as a homeostatic feedback to control the activity of PABP in cells.
Yoshida
Madoka
M
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Yoshida
Kaori
K
Kozlov
Guennadi
G
Lim
Nadia S
NS
De Crescenzo
Gregory
G
Pang
Zhiyu
Z
Berlanga
Juan Jose
JJ
Kahvejian
Avak
A
Gehring
Kalle
K
Wing
Simon S
SS
Sonenberg
Nahum
N
D025461:Feedback, Physiological; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D039102:Poly(A)-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
C488448:PAIP2 protein, human; D039102:Poly(A)-Binding Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; C117617:UBR5 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex