Regulation of processing bodies: From viruses to cancer epigenetic machinery

Kanakamani, Sunmathy; Suresh, Padmanaban S.; Venkatesh, Thejaswini

doi:10.1002/cbin.11527

Cited by 7 publications

(7 citation statements)

References 104 publications

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“…There are numerous reports of viral gene products that trigger PB disassembly, yet corresponding reports of viral gene products that stimulate PB formation are rare, suggesting that PBs possess direct antiviral function and their disassembly may favour viral replication in ways that we do not yet grasp [33,34]. Even though other RNPs, such as stress granules, have emerged as important components of our antiviral defenses that contribute to sensing virus and triggering innate immune responses, evidence to support a direct antiviral role for PBs is less well established [34][35][36][37].…”

Section: Introductionmentioning

confidence: 98%

Human coronaviruses disassemble processing bodies

et al. 2022

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A dysregulated proinflammatory cytokine response is characteristic of severe coronavirus infections caused by SARS-CoV-2, yet our understanding of the underlying mechanism responsible for this imbalanced immune response remains incomplete. Processing bodies (PBs) are cytoplasmic membraneless ribonucleoprotein granules that control innate immune responses by mediating the constitutive decay or suppression of mRNA transcripts, including many that encode proinflammatory cytokines. PB formation promotes turnover or suppression of cytokine RNAs, whereas PB disassembly corresponds with the increased stability and/or translation of these cytokine RNAs. Many viruses cause PB disassembly, an event that can be viewed as a switch that rapidly relieves cytokine RNA repression and permits the infected cell to respond to viral infection. Prior to this submission, no information was known about how human coronaviruses (CoVs) impacted PBs. Here, we show SARS-CoV-2 and the common cold CoVs, OC43 and 229E, induced PB loss. We screened a SARS-CoV-2 gene library and identified that expression of the viral nucleocapsid (N) protein from SARS-CoV-2 was sufficient to mediate PB disassembly. RNA fluorescent in situ hybridization revealed that transcripts encoding TNF and IL-6 localized to PBs in control cells. PB loss correlated with the increased cytoplasmic localization of these transcripts in SARS-CoV-2 N protein-expressing cells. Ectopic expression of the N proteins from five other human coronaviruses (OC43, MERS, 229E, NL63 and SARS-CoV) did not cause significant PB disassembly, suggesting that this feature is unique to SARS-CoV-2 N protein. These data suggest that SARS-CoV-2-mediated PB disassembly contributes to the dysregulation of proinflammatory cytokine production observed during severe SARS-CoV-2 infection.

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Section: Introductionmentioning

confidence: 98%

Human coronaviruses disassemble processing bodies

et al. 2022

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“…There are numerous reports of viral gene products that trigger PB disassembly, yet corresponding reports of viral gene products that stimulate PB formation are rare, suggesting that PBs possess direct antiviral function and their disassembly may favour viral replication in ways that we do not yet grasp [33, 34]. Even though other RNPs, such as stress granules, have emerged as important components of our antiviral defenses that contribute to sensing virus and triggering innate immune responses, evidence to support a direct antiviral role for PBs is less well established [34–37] .…”

Section: Introductionmentioning

confidence: 99%

Human coronaviruses disassemble processing bodies

Robinson

Kleer

Mulloy

et al. 2020

Preprint

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The Coronaviridae are a family of viruses with large RNA genomes. Seven coronaviruses (CoVs) have been shown to infect humans, including the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease of 2019 (COVID-19). The host response to CoV infection is complex and regulated, in part, by intracellular antiviral signaling pathways triggered in the first cells that are infected. Emerging evidence suggests that CoVs hijack these antiviral responses to reshape the production of interferons and proinflammatory cytokines. Processing bodies (PBs) are membraneless ribonucleoprotein granules that mediate decay or translational suppression of cellular mRNAs; this is particularly relevant for proinflammatory cytokine mRNA which normally reside in PBs and are repressed. Emerging evidence also suggests that PBs or their components play important direct-acting antiviral roles, providing a compelling reason for their frequent disassembly by many viruses. No information is known about how human CoVs impact PBs. Here, we provide data to show that infection with the human CoV, OC43, causes PB disassembly. Moreover, we show that several SARS-CoV-2 gene products also mediate PB loss and virus-induced PB loss correlates with elevated levels of proinflammatory cytokine mRNAs that would normally be repressed in PBs. Finally, we demonstrate that stimulating PB formation prior to OC43 infection restricts viral replication. These data suggest that SARS-CoV-2 and other CoVs disassemble PBs during infection to support viral replication and evade innate immune responses. As an unintended side effect, the disassembly of PBs enhances translation of proinflammatory cytokine mRNAs which normally reside in PBs, thereby reshaping the subsequent immune response.

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“…both pro-and anti-viral functions (56)(57)(58)(59). Here, we show for the first time that transient expression of SHFL alone triggers the disassembly of P-bodies and simultaneously the induction SG-like densities in virus-free cells.…”

Section: Discussionmentioning

confidence: 66%

“…We also identified several other RBPs that are known constituents of cytoplasmic RNP granules including both P-bodies and Stress Granules. Both granule types have gained increasing attention over the past decade as critical biophysical sites of RNA regulation that have recently been attribute both pro- and anti-viral functions ( 56–59 ). Here, we show for the first time that transient expression of SHFL alone triggers the disassembly of P-bodies and simultaneously the induction SG-like densities in virus-free cells.…”

Section: Discussionmentioning

confidence: 99%

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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Regulation of processing bodies: From viruses to cancer epigenetic machinery

Cited by 7 publications

References 104 publications

Human coronaviruses disassemble processing bodies

Human coronaviruses disassemble processing bodies

Human coronaviruses disassemble processing bodies

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

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