TY - JOUR
T1 - Competition between translation initiation factor eIF5 and its mimic protein 5MP determines non-AUG initiation rate genome-wide
AU - Tang, Leiming
AU - Morris, Jacob
AU - Wan, Ji
AU - Moore, Chelsea
AU - Fujita, Yoshihiko
AU - Gillaspie, Sarah
AU - Aube, Eric
AU - Nanda, Jagpreet
AU - Marques, Maud
AU - Jangal, Maika
AU - Anderson, Abbey
AU - Cox, Christian
AU - Hiraishi, Hiroyuki
AU - Dong, Leiming
AU - Saito, Hirohide
AU - Singh, Chingakham Ranjit
AU - Witcher, Michael
AU - Topisirovic, Ivan
AU - Qian, Shu Bing
AU - Asano, Katsura
N1 - Funding Information:
Innovative Award from Terry Johnson Cancer Center; KSU; KU-COBRE Protein Structure and Function Pilot Grant [P30GM110761]; NSF Research Grant [1412250 to K.A.]; US National Institutes of Health
Funding Information:
[R01AG042400, R01GM1222814 to S.-B.Q.]; Chelsea Moore, Sarah Gillaspie and Eric Aube were K-INBRE scholars [P20GM103418]; S.-B. Q. is a HHMI Faculty Scholar [55108556]; I.T. and M.W. are recipients of Chercheur Boursier-Junior 2 salary support from FRQ-S. KA’s visit to CiRA was funded by JSPS Fellowship for Foreign Scientist Invitation and Heiwa Nakajima Foundation (to H. Saito). Funding for open access charge: KSU open access fund. Conflict of interest statement. None declared.
Publisher Copyright:
© The Author(s) 2017.
PY - 2017/11/16
Y1 - 2017/11/16
N2 - In the human genome, translation initiation fromnon- AUG codons plays an important role in various gene regulation programs. However, mechanisms regulating the non-AUG initiation rate remain poorly understood. Here, we show that the non-AUG initiation rate is nearly consistent under a fixed nucleotide context in various human and insect cells. Yet, it ranges from <1% to nearly 100% compared to AUG translation, depending on surrounding sequences, including Kozak, and possibly additional nucleotide contexts. Mechanistically, this range of non-AUG initiation is controlled in part, by the eIF5-mimic protein (5MP). 5MP represses non-AUG translation by competing with eIF5 for the Met-tRNAi-binding factor eIF2. Consistently, eIF5 increases, whereas 5MP decreases translation ofNAT1/EIF4G2/DAP5, whose sole start codon is GUG. By modulating eIF5 and 5MP1 expression in combination with ribosome profiling we identified a handful of previously unknown non-AUG initiation sites, some of which serve as the exclusive start codons. If the initiation rate for these codons is low, then an AUG-initiated downstream ORF prevents the generation of shorter, AUGinitiated isoforms. We propose that the homeostasis of the non-AUG translatome is maintained through balanced expression of eIF5 and 5MP.
AB - In the human genome, translation initiation fromnon- AUG codons plays an important role in various gene regulation programs. However, mechanisms regulating the non-AUG initiation rate remain poorly understood. Here, we show that the non-AUG initiation rate is nearly consistent under a fixed nucleotide context in various human and insect cells. Yet, it ranges from <1% to nearly 100% compared to AUG translation, depending on surrounding sequences, including Kozak, and possibly additional nucleotide contexts. Mechanistically, this range of non-AUG initiation is controlled in part, by the eIF5-mimic protein (5MP). 5MP represses non-AUG translation by competing with eIF5 for the Met-tRNAi-binding factor eIF2. Consistently, eIF5 increases, whereas 5MP decreases translation ofNAT1/EIF4G2/DAP5, whose sole start codon is GUG. By modulating eIF5 and 5MP1 expression in combination with ribosome profiling we identified a handful of previously unknown non-AUG initiation sites, some of which serve as the exclusive start codons. If the initiation rate for these codons is low, then an AUG-initiated downstream ORF prevents the generation of shorter, AUGinitiated isoforms. We propose that the homeostasis of the non-AUG translatome is maintained through balanced expression of eIF5 and 5MP.
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U2 - 10.1093/nar/gkx808
DO - 10.1093/nar/gkx808
M3 - Article
C2 - 28981728
AN - SCOPUS:85038229640
VL - 45
SP - 11941
EP - 11953
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 20
ER -