Influenza A Virus Negative Strand RNA is Translated for CD8+ T Cell Immunosurveillance

Hickman, Heather D.; Mays, Jacqueline W.; Gibbs, James S.; Košík, Ivan; Magadán, Javier G.; Takeda, Kazuyo; Das, Suman; Reynoso, Glennys V.; Ngudiankama, Barbara F.; Wei, Jiajie; Shannon, James A.; McManus, Daniel; Yewdell, Jonathan W.

doi:10.1101/261966

Cited by 1 publication

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References 41 publications

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“…It is possible that there is no initiation at this site, or 325 that initiation occurs but at a very low level, consistent with the low overall Ribo-seq + 326 LTM P-site density at CUG322 compared to the other locations on NP. In that case, 327 more sensitive immunological assays [5,25] might be necessary to identify initiation at 328 CUG322 and other CUG codons in the high CUG NP variant. Another important 329 caveat is that LTM treatment may not effectively arrest CUG-initiating ribosomes.…”

Section: /53mentioning

confidence: 99%

“…3B), suggesting that anti-viral response as mediated by interferon-β 246 induction does not result in detectably higher number of alternate translation initiation 247 sites in influenza transcripts [6]. An important caveat to this observation is that the 248 Ribo-seq + LTM assay is likely to miss TIS that have a low frequency of initiation, but 249 could still be detectable by sensitive immunological assays [5,25].…”

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confidence: 95%

“…For 600 instance, CUG initiation could be partially refractory to capture by the translation 601 initiation inhibitor lactidomycin used in our experiments [5], or perhaps only occurs in 602 certain types of cells. In addition, even extremely low levels of translation initiation 603 that are difficult to detect by most experimental methods can generate peptides that 604 can still be recognized by T-cells [25]. A second possibility is that the selection against 605 CUG codons is due to some pressure unrelated to translation initiation.…”

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Comprehensive profiling of translation initiation in influenza virus infected cells

Machkovech

Bloom

Subramaniam

2018

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Translation can initiate at alternate, non-canonical start codons in response to stressful stimuli in mammalian cells. Recent studies suggest that viral infection and anti-viral responses alter sites of translation initiation, and in some cases, lead to production of novel immune epitopes. Here we systematically investigate the extent and impact of alternate translation initiation in cells infected with influenza virus. We perform evolutionary analyses that suggest selection against non-canonical initiation at CUG codons in influenza virus lineages that have adapted to mammalian hosts. We then use ribosome profiling with the initiation inhibitor lactidomycin to experimentally delineate translation initiation sites in a human lung epithelial cell line infected with influenza virus. We identify several candidate sites of alternate initiation in influenza mRNAs, all of which occur at AUG codons that are downstream of canonical initiation codons. One of these candidate downstream start sites truncates 14 amino acids from the N-terminus of the N1 neuraminidase protein, resulting in loss of its cytoplasmic tail and a portion of the transmembrane domain. This truncated neuraminidase protein is expressed on the cell surface during influenza virus infection, is enzymatically active, and is conserved in most N1 viral lineages. Host transcripts induced by the anti-viral response are enriched for translation initiation at non-canonical start sites and non-AUG start codons. Together, our results systematically map the landscape of translation initiation during influenza virus infection, and shed light on the evolutionary forces shaping this landscape.

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confidence: 99%

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confidence: 95%

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