010 W3310 12 - · PDF file•Cellular’IRESes –BiP –c8Myc...
Transcript of 010 W3310 12 - · PDF file•Cellular’IRESes –BiP –c8Myc...
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Transla'onLecture 10
Virology W3310/4310Spring 2012
The difficulty lies, not in the new ideas, but in escaping old ones...
-‐-‐JOHN MAYNARD KEYNES
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retroviruses
PoliovirusSindbis virus Influenza virus
VSV
reovirus
hepaNNs B virus
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• Found on most eukaryo/c mRNAs except organelle mRNAs and certain viral mRNAs
• 5'-‐7-‐methylguanosine (m7G) joined to second nucleo/de of mRNA by 5'-‐5' phosphodiester linkage
• Directs pre-‐mRNAs to processing and transport pathways, regulates mRNA turnover, required for efficient transla/on by 5'-‐end dependent mechanism
N N
N
O
HN
H2N
CH3
O
CH2 O P O PO
O-
O
O-
OHO P O CH2
O
O-
O
O O(CH3)
POO-
O CH2 O
O O(CH3)
P OOO-
5'5'
(m7)
3'
base 1
base 22'3'
5'
OH2'
3' 2'
guanosine
5’-‐cap structure
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5’-‐untranslated region
•3 – >1,000 nt in length, typically 50 – 70 nt•OWen contains RNA secondary structures; must be unwound to allow passage of ribosome
•Length and secondary structure influence translaNon efficiency
3’-‐untranslated region
•Can regulate translaNon iniNaNon, translaNon efficiency, mRNA stability
•poly(A) tail, necessary for efficient translaNon
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TranslaNonal machinery: Ribosomes
RNA=pink, yellowProtein=blue
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TranslaNonal machinery: tRNAs
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Transla'onal machinery
• Ribosomes• tRNAs• ini/a/on proteins (eIF)• elonga/on proteins (eEF)• termina/on proteins (eRF)
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Two mechanisms of ini'a'on
• 5’-‐dependent iniNaNon (most mRNAs): iniNaNon complex binds to 5’-‐cap structure, and scans in a 3’-‐direcNon to the iniNaNon codon
• Internal ribosome entry: iniNaNon complex binds at, or just upstream of, the iniNaNon codon
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5’-‐end dependent ini'a'on
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Other mechanisms for decoding have been discovered in virus-‐infected cells
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Ribosome shun'ng
-‐80 kcal/mole
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direct transloca'on
5' scanning
Ribosome shun'ng–35s mRNAs of plant pararetroviruses
–late adenovirus mRNAs
–P/C mRNA of Sendai virus
ShunNng is predicted to decrease dependence of mRNAs for eIF4F during iniNaNon by reducing the need for mRNA unwinding
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Internal ini'a'on
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IRES = internal ribosome entry site17
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eIF4G footprint
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Hepa''s C virus IRES
• 40S subunit binds IRES without iniNaNon proteins
• eIF3 binds IRES, needed for subunit joining
• HCV coding sequence is part of the IRES
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all eIFs
all eIFs except eIF4E
eIF2, eIF3
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• Viral IRESes– Picornaviruses– Flaviviruses (hepaNNs
C virus)– PesNviruses (bovine
viral diarrhea virus, classical swine fever virus)
– Retroviruses (SIV, MMLV, HTLV, FLV)
– Insect picorna-‐like viruses (cricket paralysis virus, PlauNa stali intesNne virus)
• Cellular IRESes– BiP– c-‐Myc– Antennapaedia– Ornithine decarboxylase– Fibroblast growth factor– Vascular endothelial growth factor
– protein kinase p58PITSLRE
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AminoacylPepNdylExit
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Methionine-‐independent ini'a'on
• Can assemble 80S ribosomes without any eIFs or Met-‐tRNAi
• RNA mimics tRNAi
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RNA genome of cricket paralysis virus
Binds 40S ribosome independent of iniNaNon proteins
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Maximizing the coding capacity of the viral genome
• Polyprotein (Picornaviridae, Flaviviridae, Togaviridae, Arenaviridae, Bunyaviridae, Retroviridae)
• Internal iniNaNon (IRES) (Picornaviridae, Flaviviridae)
• Leaky scanning (Retroviridae, Paramyxoviridae)
• Re-‐iniNaNon of translaNon (Orthomyxoviridae, Herpesviridae)
• Suppression of terminaNon (Retroviridae, Togaviridae)
• Ribosomal frameshiWing (Retroviridae)
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Polyprotein synthesis
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Leaky scanning
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Suppression of termina'on
eRF1 and eRF3 recognize all 3 stop codons (UAA, UAG, UGA
But occasionally stop codons may be recognized by a charged tRNA
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Suppression of termina'on
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Suppression of termina'on
• Suppressor tRNAs: recognize terminaNon codons and insert specific amino acid, e.g. suppressor tRNA that inserts selenocysteine for UGA
• Normal tRNAs may misread terminaNon codons
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Ribosomal frameshiOing
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Model for -‐1 frameshiOing
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Regula'on of transla'on in virus-‐infected cells
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eIF2α kinases
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PKR
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PKR and cellular an'viral response
• PKR induced and acNvated by virus infecNon
• Leads to inhibiNon of host translaNon, apoptosis
• Different viral mechanisms have evolved to inacNvate the PKR pathway
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Adenovirus VA RNA I prevents ac'va'on of PKR
dsRNA
active
VA RNA I
eIF2α subunitphosphorylation
P P
inactive
PKR
inactive
no phosphorylation of eIF2α subunit
active protein synthesis
protein synthesis inhibited
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Vaccinia virus encoded pseudosubstrates mimic eIF2α
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Targets of viral inhibitors of eIF2α phosphoryla'on
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Regula'on of eIF4F ac'vity
• eIF4F = eIF4G + eIF4E + eIF4A
• Cleavage of eIF4GI, II in cells infected with picornaviruses
• Cleavage by proteinases 2Apro, Lpro
• Viral IRES does not require intact eIF4G
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microRNA (miRNA)
• Small non-‐coding RNAs encoded within the viral or cellular genome
• Transcribed as 60-‐70 nt pre-‐miRNA by either pol II or pol III
• Processed by the cell to ~21 nt
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miRNA
• >1000 human miRNAs, regulate ~60% of protein-‐coding genes
• Control gene expression post-‐transcripNonally via either repression of translaNon or mRNA degradaNon
• Mainly target 3’-‐UTR of RNA
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miRNA
• miRNA funcNon in a complex, the miRNPs, composed of Ago, Dicer, and TRBP
• Complementarity to 3’-‐UTR determines whether the mRNA is degraded or translaNon is repressed
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Two ways that miRNAs regulate transla'on
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Viruses and cellular miRNAs
• miR-‐122 is a liver-‐specific miRNA required for HCV replicaNon
• miRNAs target viral or cellular genes needed for viral replicaNon
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Virus-‐encoded miRNAs
• Viral miRs block apoptosis, facilitate immune escape, prevent cell cycle arrest, promote latency
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