TY - JOUR
T1 - LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for microRNA-mediated gene silencing
AU - James, Victoria
AU - Zhang, Yining
AU - Foxler, Daniel E.
AU - De Moor, Cornelia H.
AU - Kong, Yi Wen
AU - Webb, Thomas M.
AU - Self, Tim J.
AU - Feng, Yungfeng
AU - Lagos, Dimitrios
AU - Chu, Chia Ying
AU - Rana, Tariq M.
AU - Morley, Simon J.
AU - Longmore, Gregory D.
AU - Bushell, Martin
AU - Sharp, Tyson V.
PY - 2010/7/13
Y1 - 2010/7/13
N2 - In recent years there have been major advances with respect to the identification of the protein components and mechanisms of micro-RNA (miRNA) mediated silencing. However, the complete and precise repertoire of components and mechanism(s) of action remain to be fully elucidated. Herein we reveal the identification of a family of three LIM domain-containing proteins, LIMD1, Ajuba and WTIP (Ajuba LIM proteins) as novel mammalian processing body (P-body) components, which highlight a novel mechanism of miRNA-mediated gene silencing. Furthermore, we reveal that LIMD1, Ajuba, and WTIP bind to Ago1/2, RCK, Dcp2, and eIF4E in vivo, that they are required for miRNA-mediated, but not siRNA-mediated gene silencing and that all three proteins bind to the mRNA 5′ m7GTP cap-protein complex. Mechanistically, we propose the Ajuba LIM proteins interact with the m7GTP cap structure via a specific interaction with eIF4E that prevents 4EBP1 and eIF4G interaction. In addition, these LIM-domain proteins facilitate miRNA-mediated gene silencing by acting as an essential molecular link between the translationally inhibited eIF4E-m7GTP-5′cap and Ago1/2 within the miRISC complex attached to the 3′-UTR of mRNA, creating an inhibitory closed-loop complex.
AB - In recent years there have been major advances with respect to the identification of the protein components and mechanisms of micro-RNA (miRNA) mediated silencing. However, the complete and precise repertoire of components and mechanism(s) of action remain to be fully elucidated. Herein we reveal the identification of a family of three LIM domain-containing proteins, LIMD1, Ajuba and WTIP (Ajuba LIM proteins) as novel mammalian processing body (P-body) components, which highlight a novel mechanism of miRNA-mediated gene silencing. Furthermore, we reveal that LIMD1, Ajuba, and WTIP bind to Ago1/2, RCK, Dcp2, and eIF4E in vivo, that they are required for miRNA-mediated, but not siRNA-mediated gene silencing and that all three proteins bind to the mRNA 5′ m7GTP cap-protein complex. Mechanistically, we propose the Ajuba LIM proteins interact with the m7GTP cap structure via a specific interaction with eIF4E that prevents 4EBP1 and eIF4G interaction. In addition, these LIM-domain proteins facilitate miRNA-mediated gene silencing by acting as an essential molecular link between the translationally inhibited eIF4E-m7GTP-5′cap and Ago1/2 within the miRISC complex attached to the 3′-UTR of mRNA, creating an inhibitory closed-loop complex.
KW - Argonaute
KW - P-bodies
KW - Tumor suppressor
KW - eIF4E
KW - mGTP cap
UR - http://www.scopus.com/inward/record.url?scp=77955464737&partnerID=8YFLogxK
U2 - 10.1073/pnas.0914987107
DO - 10.1073/pnas.0914987107
M3 - Article
C2 - 20616046
AN - SCOPUS:77955464737
SN - 0027-8424
VL - 107
SP - 12499
EP - 12504
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 28
ER -