C19orf66 Inhibits Japanese Encephalitis Virus Replication by Targeting -1 PRF and the NS3 Protein

Yu, Du; Zhao, Yundi; Pan, Junhui; Yang, Xingmiao; Liang, Zhenjie; Xie, Shengda; Cao, Rui

doi:10.1007/s12250-021-00423-6

Cited by 20 publications

(36 citation statements)

References 51 publications

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“…Further exploration is required to determine if SHFL also restricts the translation of ORF57. Or, as suggested by recent SHFL studies in ZIKV, PEDV, and JEV, SHFL could be coordinating with lysosomal or ubiquitinoylation pathways to degrade ORF57 (22,25,26).…”

Section: Discussionmentioning

confidence: 90%

“…SHFL is an interferon stimulated gene (ISG) that is demonstrably a vital piece of the innate immune response to viral infection, capable of suppressing the replication of multiple DNA, RNA, and retroviruses (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Studies of SHFL function over the past 5 years have revealed its multifaceted capacity to negatively modulate viral RNA stability, viral gene translation, and even viral protein stability through interactions with cellular co-factors that coordinate these processes such as cytoplasmic poly(A) binding protein 1 (PABPC1), La Ribonucleoprotein Domain Family Member 1 (LARP1) and the RNA helicase MOV10 (19,20).…”

Section: Introductionmentioning

confidence: 99%

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Shiftless Restricts Viral Gene Expression and Influences RNA Granule Formation during KSHV lytic replication

Rodríguez

Mehrmann

Muller

2022

Preprint

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Herpesviral infection reflects thousands of years of co-evolution and the constant struggle between virus and host for control of cellular gene expression. During Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication, the virus rapidly seizes control of host gene expression machinery by triggering a massive RNA decay event via a virally-encoded endoribonuclease, SOX. This virus takeover strategy decimates close to 80% of cellular transcripts, reallocating host resources toward viral replication. The host cell, however, is not entirely passive in this assault on RNA stability. A small pool of host transcripts that actively evade SOX cleavage has been identified over the years. One such "escapee", C19ORF66 (herein referred to as Shiftless - SHFL) encodes a potent anti-viral protein capable of restricting the replication of multiple DNA, RNA, and retroviruses including KSHV. Here, we show that SHFL restricts KSHV replication by targeting the expression of critical viral early genes, including the master transactivator protein, KSHV ORF50, and thus subsequently the entire lytic gene cascade. Consistent with previous reports, we found the SHFL interactome throughout KSHV infection is dominated by RNA-binding proteins that influence both translation and protein stability, including the viral protein ORF57, a crucial regulator of viral RNA fate. We next show that SHFL affects cytoplasmic RNA granule formation, triggering the disassembly of processing bodies. Taken together, our findings provide insights into the complex relationship between RNA stability, RNA granule formation, and the anti-viral response to KSHV infection.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Shiftless Restricts Viral Gene Expression and Influences RNA Granule Formation during KSHV lytic replication

Rodríguez

Mehrmann

Muller

2022

Preprint

View full text Add to dashboard Cite

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“…In addition, antiviral host proteins can also affect viral mRNA translation and frameshifting. For example, an ISG product, known as C19orf66 (Shiftless), has been demonstrated to impair HIV-1 and Japanese encephalitic virus replication through inhibition of PRF ( 44 , 45 ) and dengue virus replication through inhibition of viral translation ( 46 ). Furthermore, C19orf66 associates with host ribosomes, and it can inhibit PRF of different coronaviruses, including SARS-CoV-2 in vitro ( 47 ), and has been found to associate with SARS-CoV-2 RNAs in cells ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

The Translational Landscape of SARS-CoV-2-infected Cells Reveals Suppression of Innate Immune Genes

Puray-Chavez

Lee

Tenneti

et al. 2022

mBio

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“…In nearly every context, this protein was identified as a broad-spectrum anti-viral factor whose expression is upregulated in response to Type I interferon (IFN) induction and generally viral infection. From these studies, several unique identifiers have been attributed to the C19orf66 gene product including FLJ11286 (genomic location), Repressor of Yield of Dengue Virus (RyDEN), Suppressor of Viral Activity-1 (SVA-1), Interferon Regulated Anti-Viral gene (IRAV), and more recently Shiftless (SFL/SHFL) with SHFL finally approved for its official gene symbol [10][11][12][13][14][15][16][17][18][19][20]. SHFL expression can often vary dramatically between cell types as demonstrated by Balinsky and colleagues [11].…”

Section: Shiftless: An Isg Of Many Namesmentioning

confidence: 99%

“…An increasing number of large-scale screens have independently identified SHFL as both an anti-viral factor and downstream effector of the Type I, II, and III interferon response to viral infection [2][3][4][5][6][7][8][9]. Some studies have gone even further to characterize SHFL as a potent, broad-spectrum restriction factor for a growing list of DNA, RNA, and Retroviruses (Summarized in Table 1) [8,[10][11][12][13][14][15][16][17][18][19][20]. Many ISGs have evolved to target viral gene expression as it is often the primary battleground that nearly every viral replication steps depend upon.…”

Section: Introductionmentioning

confidence: 99%

Shiftless, a Critical Piece of the Innate Immune Response to Viral Infection

Rodríguez

Muller

2022

Viruses

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Since its initial characterization in 2016, the interferon stimulated gene Shiftless (SHFL) has proven to be a critical piece of the innate immune response to viral infection. SHFL expression stringently restricts the replication of multiple DNA, RNA, and retroviruses with an extraordinary diversity of mechanisms that differ from one virus to the next. These inhibitory strategies include the negative regulation of viral RNA stability, translation, and even the manipulation of RNA granule formation during viral infection. Even more surprisingly, SHFL is the first human protein found to directly inhibit the activity of the -1 programmed ribosomal frameshift, a translation recoding strategy utilized across nearly all domains of life and several human viruses. Recent literature has shown that SHFL expression also significantly impacts viral pathogenesis in mouse models, highlighting its in vivo efficacy. To help reconcile the many mechanisms by which SHFL restricts viral replication, we provide here a comprehensive review of this complex ISG, its influence over viral RNA fate, and the implications of its functions on the virus-host arms race for control of the cell.

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C19orf66 Inhibits Japanese Encephalitis Virus Replication by Targeting -1 PRF and the NS3 Protein

Cited by 20 publications

References 51 publications

Shiftless Restricts Viral Gene Expression and Influences RNA Granule Formation during KSHV lytic replication

Shiftless Restricts Viral Gene Expression and Influences RNA Granule Formation during KSHV lytic replication

The Translational Landscape of SARS-CoV-2-infected Cells Reveals Suppression of Innate Immune Genes

Shiftless, a Critical Piece of the Innate Immune Response to Viral Infection

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