Eukaryotic initiation factor 3

eIF3 stimulates nearly all steps of translation initiation. eIF3 also appears to participate in other phases of translation, such as recycling, where it promotes the splitting of post-termination ribosomes.{{cite journal|last1=Pisarev|first1=Andrey V.|last2=Hellen|first2=Christopher U. T.|last3=Pestova|first3=Tatyana V.|title=Recycling of eukaryotic post-termination ribosomal complexes|journal=Cell|date=2007|volume=131|issue=2|pages=286–99|doi=10.1016/j.cell.2007.08.041|pmid=17956730|pmc=2651563}} In specialized cases of reinitiation following uORFs, eIF3 may remain bound to the ribosome through elongation and termination to promote subsequent initiation events.{{cite journal|last1=Sonenberg|first1=Nahum|last2=Hinnebusch|first2=Alan G.|title=Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets|journal=Cell|date=2009|volume=136|issue=4|pages=731–745|doi=10.1016/j.cell.2009.01.042|pmid=19239892|url= |pmc=3610329}} Research has also indicated that eIF3 plays a role in programmed stop codon readthrough in yeast, by interacting with pre-termination complexes and interfering with decoding.{{cite journal|last1=Beznoskova|first1=Petra|last2=Wagner|first2=Susan|last3=Jansen|first3=Myrte Esmeralda|last4=von der Haar|first4=Tobias|last5=Valasek|first5=Leos Shivaya|title=Translation initiation factor eIF3 promotes programmed stop codon readthrough|journal=Nucleic Acids Res.|date=2015|volume=43|issue=10|pages=5099–5111|doi=10.1093/nar/gkv421|pmid=25925566|pmc=4446449}}

eIF3 binds the small ribosomal subunit (40S) at and near its solvent side and serves as a scaffold for several other initiation factors, the auxiliary factor DHX29, and mRNA. eIF3 is a component of the multifactor complex (MFC) and 43S and 48S preinitiation complexes (PICs). The interactions of eIF3 with other initiation factors can vary amongst species; for example, mammalian eIF3 directly interacts with the eIF4F complex (via eIF4G), while budding yeast lacks this connection. However, both mammalian and yeast eIF3 independently bind eIF1, eIF4B, and eIF5.{{cite journal|last1=Jackson|first1=Richard J.|last2=Hellen|first2=Christopher U. T.|last3=Pestova|first3=Tatyana V.|title=The mechanism of eukaryotic translation initiation and principles of its regulation|journal=Nat. Rev. Mol. Cell Biol.|date=2010|volume=11|issue=2|pages=113–127|doi=10.1038/nrm2838|pmid=20094052|pmc=4461372}}

Several subunits of eIF3 contain RNA recognition motifs (RRMs) and other RNA binding domains to form a multisubunit RNA binding interface through which eIF3 interacts with cellular and viral IRES mRNA, including the HCV IRES. eIF3 has also been shown to specifically bind m⁶A modified RNA within 5'UTRs to promote cap-independent translation.{{cite journal|last1=Meyer|first1=Kate D.|last2=Patil|first2=Deepak P.|last3=Zhou|first3=Jun|last4=Zinoviev|first4=Alexandra|last5=Skabkin|first5=Maxim A.|last6=Elemento|first6=Olivier|last7=Pestova|first7=Tatyana V.|last8=Qiang|first8=Shu-Bing|last9=Jaffrey|first9=Samie R.|title=5' UTR m6A Promotes Cap-Independent Translation|journal=Cell|date=November 2015|volume=163|issue=4|pages=999–1010|doi=10.1016/j.cell.2015.10.012|pmid=26593424|pmc=4695625|url=}}

All five core subunits of budding yeast's eIF3 are present in heat-induced stress granules, along with several other translation factors.{{cite journal|last1=Wallace|first1=Edward W.J.|last2=Kear-Scott|first2=Jamie L.|last3=Pilipenko|first3=Evgeny V.|last4=Schwartz|first4=Michael H.|last5=Laskowsk|first5=Pawel R.|last6=Rojek|first6=Alexander E.|last7=Katansk|first7=Christopher D.|last8=Riback|first8=Joshua A.|last9=Dion|first9=Michael F.|last10=Franks|first10=Alexander M.|author-link11=Edoardo Airoldi|last11=Airoldi|first11=Edoardo M.|last12=Pan|first12=Tao|last13=Budnik|first13=Bogdan A.|last14=Drummond|first14=D. Allan|title=Reversible, Specific, Active Aggregates of Endogenous Proteins Assemble upon Heat Stress|journal=Cell|date=2015|volume=162|issue=6|pages=1286–1298|doi=10.1016/j.cell.2015.08.041|pmid=26359986|pmc=4567705}}

A functional eIF3 complex can be purified from native sources, or reconstituted from recombinantly expressed subunits.{{cite journal|last1=Zhou|first1=Min|last2=Sandercock|first2=Alan M.|last3=Fraser|first3=Christopher S.|last4=Ridlova|first4=Gabriela|last5=Stephens|first5=Elaine|last6=Schenauer|first6=Matthew R.|last7=Yokoi-Fong|first7=Theresa|last8=Barsky|first8=Daniel|last9=Leary|first9=Julie A.|last10=Hershey|first10=John W.|last11=Doudna|first11=Jennifer A.|last12=Robinson|first12=Carol V.|title=Mass spectrometry reveals modularity and a complete subunit interaction map of the eukaryotic translation factor eIF3|journal=Proc. Natl. Acad. Sci.|date=Nov 2008|volume=105|issue=47|pages=18139–44|doi=10.1073/pnas.0801313105|pmid=18599441|pmc=2587604|doi-access=free}}{{cite journal|last1=Sun|first1=Chaomin|last2=Todorovic|first2=Aleksandar|last3=Querol-Audi|first3=Jordi|last4=Bai|first4=Yun|last5=Villa|first5=Nancy|last6=Snyder|first6=Monica|last7=Ashchyan|first7=John|last8=Lewis|first8=Christopher S.|last9=Hartland|first9=Abbey|last10=Gradia|first10=Scott|last11=Fraser|first11=Christopher S.|last12=Doudna|first12=Jennifer A.|last13=Nogales|first13=Eva|last14=Cate|first14=Jamie H. D.|title=Functional reconstitution of human eukaryotic translation initiation factor 3 (eIF3)|journal=Proc. Natl. Acad. Sci.|date=2011|volume=108|issue=51|pages=20473–20478|doi=10.1073/pnas.1116821108|pmid=22135459|pmc=3251073|bibcode=2011PNAS..10820473S|doi-access=free}} Individual subunits have been structurally characterized by X-ray crystallography and NMR, while complexes have been characterized by Cryo-EM.{{cite journal|last1=Liu|first1=Yi|last2=Neumann|first2=Piotr|last3=Kuhle|first3=Berhard|last4=Monecke|first4=Thomas|last5=Schell|first5=Stephanie|last6=Chari|first6=Ashwin|last7=Ficner|first7=Ralph|title=Translation Initiation Factor eIF3b Contains a Nine-Bladed b-Propeller and Interacts with the 40S Ribosomal Subunit|journal=Structure|date=2014|volume=22|issue=6|pages=923–930|doi=10.1016/j.str.2014.03.010|pmid=24768115|doi-access=free}}{{cite journal|last1=ElAntak|first1=Latifa|last2=Wagner|first2=Susan|last3=Herrmannova|first3=Anna|last4=Karaskova|first4=Martina|last5=Rutkai|first5=Edit|last6=Lukavsky|first6=Peter J.|last7=Valasek|first7=Leos|title=The Indispensable N-Terminal Half of eIF3j/HCR1 Cooperates with its Structurally Conserved Binding Partner eIF3b/PRT1-RRM and with eIF1A in Stringent AUG Selection|journal=J. Mol. Biol.|date=2010|volume=396|issue=4|pages=1097–1116|doi=10.1016/j.jmb.2009.12.047|pmid=20060839|pmc=2824034}}{{cite journal|last1=Siridechadilok|first1=Bunpote|last2=Fraser|first2=Christopher S.|last3=Hall|first3=Richard J.|last4=Doudna|first4=Jennifer A.|last5=Nogales|first5=Eva|title=Structural Roles for Human Translation Factor eIF3 in Initiation of Protein Synthesis|journal=Science|date=2005|volume=310|issue=5753|pages=1513–1515|doi=10.1126/science.1118977|pmid=16322461|bibcode=2005Sci...310.1513S|s2cid=6341705}} No structure of complete human eIF3 is available, but the nearly-full complex has been determined at medium resolution in the context of the 43S PIC. The structural core of mammalian eIF3 is often described as a five-lobed particle with anthropomorphic features, composed largely of the PCI/MPN octamer. The PCI domains are named for structural similarities between the proteasome cap (P), the COP9 signalosome (C), and eIF3 (I), while the MPN domains are named for structural similarity to the Mpr1-PadI N-terminal domains.

eIF3 serves as a hub for cellular signaling through S6K1 and mTOR/Raptor.{{cite journal|last1=Holz|first1=Marina K.|last2=Ballif|first2=Bryan A.|last3=Gygi|first3=Steven P.|last4=Blenis|first4=John|title=mTOR and S6K1 Mediate Assembly of the Translation Preinitiation Complex through Dynamic Protein Interchange and Ordered Phosphorylation Events|journal=Cell|date=2005|volume=123|issue=4|pages=569–580|doi=10.1016/j.cell.2005.10.024|pmid=16286006|doi-access=free}} In particular, eIF3 is bound by S6K1 in its inactive state, and activated mTOR/Raptor binds to eIF3 and phosphorylates S6K1 to promote its release from eIF3. Phosphorylated S6K1 is then free to phosphorylate a number of its own targets, including eIF4B, thus serving as a mechanism of translational control.

Individual subunits of eIF3 are overexpressed (a, b, c, h, i, and m) and underexpressed (e, f) in multiple human cancers. In breast cancer and malignant prostate cancer, eIF3h is overexpressed.{{cite journal|doi=10.1146/annurev-cancerbio-030419-033420|doi-access=free|title=The Role of Translation Control in Tumorigenesis and Its Therapeutic Implications|year=2020|last1=Xu|first1=Yichen|last2=Ruggero|first2=Davide|journal=Annual Review of Cancer Biology|volume=4|pages=437–457}} eIF3 has also been shown to bind a specific set of cell proliferation mRNAs and regulate their translation.{{Cite journal|title = eIF3 targets cell-proliferation messenger RNAs for translational activation or repression|journal = Nature|year = 2015|issn = 0028-0836|pmid = 25849773 |pages = 111–114|volume = 522|issue = 7554|doi=10.1038/nature14267|language = en|first1 = Amy S.Y.|last1 = Lee|first2 = Philip J.|last2 = Kranusch|first3 = Jamie H.D.|last3 = Cate|pmc=4603833|bibcode = 2015Natur.522..111L}} eIF3 also functions in the life cycles of a number of important human pathogens, including HIV and HCV. In particular, the d-subunit of eIF3 is a substrate of HIV protease, and genetic knockdown of eIF3 subunits d, e, or f results in increased viral infectivity for unknown reasons.{{cite journal|last1=Jäger|first1=Stefanie|last2=Cimermancic|first2=Peter|last3=Gulbahce|first3=Natali|last4=Johnson|first4=Jeffrey R.|last5=McGovern|first5=Kathryn E.|last6=Clarke|first6=Starlynn C.|last7=Shales|first7=Michael|last8=Mercenne|first8=Gaelle|last9=Pache|first9=Lars|last10=Li|first10=Kathy|last11=Hernandez|first11=Hilda|last12=Jang|first12=Gwendolyn M.|last13=Roth|first13=Shoshannah L.|last14=Akiva|first14=Eyal|last15=Marlett|first15=John|last16=Stephens|first16=Melanie|last17=D’Orso|first17=Ivan|last18=Fernandes|first18=Jason|last19=Fahey|first19=Marie|last20=Mahon|first20=Cathal|last21=O’Donoghue|first21=Anthony J.|last22=Todorovic|first22=Aleksandar|last23=Morris|first23=John H.|last24=Maltby|first24=David A.|last25=Alber|first25=Tom|last26=Cagney|first26=Gerard|last27=Bushman|first27=Frederic D.|last28=Young|first28=John A.|last29=Chanda|first29=Sumit K.|last30=Sundquist|first30=Wesley I.|last31=Kortemme|first31=Tanja|author31-link=Tanja Kortemme|last32=Hernandez|first32=Ryan D.|last33=Craik|first33=Charles S.|last34=Burlingame|first34=Alma|last35=Sali|first35=Andrej|last36=Frankel|first36=Alan D.|last37=Krogan|first37=Nevan J.|title=Global landscape of HIV–human protein complexes|journal=Nature|year=2011|issn=0028-0836|doi=10.1038/nature10719|pmid=22190034|pmc=3310911|volume=481|issue=7381|pages=365–70}}

The eIF3 subunits exist at equal stoichiometry within the complex, with the exception of eIF3J, which is loosely bound and non-essential for viability in several species.{{cite journal|last1=Valasek|first1=Leos|last2=Hasek|first2=Jiri|last3=Trachsel|first3=Hans|last4=Imre|first4=Esther Maria|last5=Ruis|first5=Helmut|title=The Saccharomyces cerevisiae HCR1 Gene Encoding a Homologue of the p35 Subunit of Human Translation Initiation Factor 3 (eIF3) Is a High Copy Suppressor of a Temperature-sensitive Mutation in the Rpg1p Subunit of Yeast eIF3|journal=J. Biol. Chem.|date=1999|volume=274|issue=39|pages=27567–72|doi=10.1074/jbc.274.39.27567|pmid=10488093|doi-access=free}}{{cite journal|last1=Smith|first1=M. Duane|last2=Yu|first2=Gu|last3=Querol-Audí|first3=Jordi|last4=Vogan|first4=Jacob M.|last5=Nitido|first5=Adam|last6=Cate|first6=Jamie H.D.|title=Human-Like Eukaryotic Translation Initiation Factor 3 from Neurospora crassa|journal=PLOS ONE |date=November 2013|volume=8|issue=11|page=e78715|doi=10.1371/journal.pone.0078715|pmid=24250809|pmc=3826745|bibcode=2013PLoSO...878715S|doi-access=free}} The subunits were originally organized alphabetically by molecular weight in mammals (A as the highest), but the arrangement of molecular weight can vary between species.{{cite journal|last1=Browning|first1=Karen S.|last2=Gallie|first2=Daniel R.|last3=Hershey|first3=John W.B.|last4=Maitra|first4=Umadas|last5=Merrick|first5=William C.|last6=Norbury|first6=Chris|title=Unified nomenclature for the subunits of eukaryotic initiation factor 3|journal=Trends Biochem. Sci.|date=May 2001|volume=26|issue=5|page=284|doi=10.1016/S0968-0004(01)01825-4|pmid=11426420}}

{{note label|rounding|A|A}}Molecular weight of human subunits from Uniprot.

• Eukaryotic translation
• 40S ribosomal subunit
• 43S preinitiation complex
• DHX29

{{Reflist}}

{{MolBioGeneExp}}

{{GeneticTranslation}}

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{{DEFAULTSORT:Eukaryotic Translation}}

Category:Protein biosynthesis

Category:Gene expression

Category:Protein complexes

Category:RNA-binding proteins