RNA-binding protein isoforms ZAP-S and ZAP-L have distinct antiviral and immune resolution functions

Schwerk, Johannes; Soveg, Frank; Ryan, Andrew P; Thomas, Kerri R.; Hatfield, Lauren D.; Ozarkar, Snehal; Forero, Adriana; Kell, Alison; Roby, Justin A; So, Lomon; Hyde, Jennifer; Gale, Michael; Daugherty, Matthew D.; Savan, Ram

doi:10.1038/s41590-019-0527-6

Cited by 99 publications

(154 citation statements)

References 46 publications

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“…More recent data indicate that ZAPS may also reduce IFN mRNA by binding to the 3 ′ UTR of IFN mRNA and targeting it for degradation ( Fig. 1A; Schwerk et al 2019). It is conceivable that ZAP-S uses both functions but in a context-dependent manner.…”

Section: Ccch Znf Parpsmentioning

confidence: 97%

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The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

et al. 2020

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Poly-adenosine diphosphate-ribose polymerases (PARPs) promote ADP-ribosylation, a highly conserved, fundamental posttranslational modification (PTM). PARP catalytic domains transfer the ADP-ribose moiety from NAD+ to amino acid residues of target proteins, leading to mono- or poly-ADP-ribosylation (MARylation or PARylation). This PTM regulates various key biological and pathological processes. In this review, we focus on the roles of the PARP family members in inflammation and host–pathogen interactions. Here we give an overview the current understanding of the mechanisms by which PARPs promote or suppress proinflammatory activation of macrophages, and various roles PARPs play in virus infections. We also demonstrate how innovative technologies, such as proteomics and systems biology, help to advance this research field and describe unanswered questions.

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Section: Ccch Znf Parpsmentioning

confidence: 97%

“…ZAPL contains the inactive PARP or catalytic domain, while ZAPS does not. ZAPL tends to have greater antiviral activity, and this may be due, at least in part, to prenylation of the PARP domain (Charron et al 2013;Schwerk et al 2019). In addition to the PARP domain, ZAP contains four ZnF-binding domains and a single WWE domain.…”

Section: Ccch Znf Parpsmentioning

confidence: 99%

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

et al. 2020

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“…In addition to viral mRNA transcripts, ZAP has also been described to mediate degradation of specific cellular transcripts (Schwerk et al, 2019;Todorova et al, 2014). Indeed, we identified two human transcripts whose stability was influenced by ZAP, TNFRSF10D, encoding the TRAIL receptor 4 (TRAILR4), and ZMAT3, encoding the zinc finger matrin-type protein 3 (also known as zinc finger protein Wig-1).…”

Section: Discussionmentioning

confidence: 99%

“…Hence, we propose that ZAP may bind transcripts via motifs other than CG-rich sequences, e.g. AU-rich elements, which can be bound by ZAP (Odon et al, 2019;Schwerk et al, 2019), or via more specific motifs that have yet to be identified. CLIP-seq assays are challenging to perform in the context of infection, but are a desirable approach to prove direct interaction between ZAP and viral transcripts.…”

Section: Discussionmentioning

confidence: 99%

“…However, another possibility is the binding of ZAP to AU-dinucleotides. Although one study claimed that ZAP does not recognise any of the three types of AU-rich elements (AREs) and concluded that ZAP may modulate stability of non-ARE-containing mRNAs (Guo et al, 2004), recent publications described ZAP target specificity for sequences enriched for AU-rich dinucleotides (Odon et al, 2019;Schwerk et al, 2019). Taken together, while there is solid data indicating ZAP recognition of CG-dinucleotide containing RNA, it is feasible that the presence of several other zinc finger motifs in the ZAP protein broadens its target specificity.…”

Section: Introductionmentioning

confidence: 99%

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The zinc finger antiviral protein ZAP destabilises viral transcripts and restricts human cytomegalovirus

Gonzalez-Perez

Stempel

Wyler

et al. 2020

Preprint

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Interferon-stimulated gene products (ISGs) play a crucial role in early infection control. The ISG zinc finger CCCH-type antiviral protein 1 (ZAP/ZC3HAV1) antagonises several RNA viruses by binding to CG-rich RNA sequences, whereas its effect on DNA viruses is largely unknown. Here, we decipher the role of ZAP in the context of human cytomegalovirus (HCMV) infection, a β-herpesvirus that is associated with high morbidity in immunosuppressed individuals and newborns. We show that expression of the two major isoforms of ZAP, the long (ZAP-L) and short (ZAP-S), is induced during HCMV infection and that both negatively affect HCMV replication. Transcriptome and proteome analyses demonstrated that the expression of ZAP decelerates the progression of HCMV infection. SLAM-sequencing revealed that ZAP restricts HCMV at early stages of infection by destabilising a distinct subset of viral transcripts with low CG content. In summary, this report provides evidence of an important antiviral role for ZAP in host defense against HCMV infection and highlights its differentiated function during DNA virus infection.

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The Role of Ribonucleases in RNA Damage, Inactivation and Degradation

Hia

Takeuchi

2021

RNA Damage and Repair

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RNA-binding protein isoforms ZAP-S and ZAP-L have distinct antiviral and immune resolution functions

Cited by 99 publications

References 46 publications

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

The zinc finger antiviral protein ZAP destabilises viral transcripts and restricts human cytomegalovirus

The Role of Ribonucleases in RNA Damage, Inactivation and Degradation

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