Viral Manipulations of the Cullin-RING Ubiquitin Ligases

Liu, Ying; Tan, Xu

doi:10.1007/978-981-15-1025-0_7

Cited by 16 publications

(12 citation statements)

References 88 publications

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“…Such unique allosteric switches, as revealed by our structural analyses, may provide opportunities for therapeutic targeting specificity distinguishing otherwise homologous complexes. This may be particularly relevant for CRL5s and ARIH2, which regulate immune pathways, and are conscripted by several viruses to promote infection [29][30][31][32]50 .…”

Section: Discussionmentioning

confidence: 99%

“…The importance of CUL5-RBX2-specific regulation is underscored by its pathological hijacking by HIV-1. HIV-1 replication depends on redirecting cellular ubiquitylation pathways to degrade host restriction factors 29 . HIV-1 Vif conscripts the host protein CBFβ to form a heterodimeric BC-box receptor, which assembles into a CRL5 Vif-CBFβ E3 that ubiquitylates APOBEC3-family restriction factors 30 – 32 .…”

Section: Mainmentioning

confidence: 99%

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CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation

et al. 2021

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An emerging mechanism of ubiquitylation involves partnering of two distinct E3 ligases. In the best-characterized E3-E3 pathways, ARIH-family RING-between-RING (RBR) E3s ligate ubiquitin to substrates of neddylated cullin-RING E3s. The E3 ARIH2 has been implicated in ubiquitylation of substrates of neddylated CUL5-RBX2-based E3s, including APOBEC3-family substrates of the host E3 hijacked by HIV-1 virion infectivity factor (Vif). However, the structural mechanisms remained elusive. Here structural and biochemical analyses reveal distinctive ARIH2 autoinhibition, and activation on assembly with neddylated CUL5-RBX2. Comparison to structures of E3-E3 assemblies comprising ARIH1 and neddylated CUL1-RBX1-based E3s shows cullin-specific regulation by NEDD8. Whereas CUL1-linked NEDD8 directly recruits ARIH1, CUL5-linked NEDD8 does not bind ARIH2. Instead, the data reveal an allosteric mechanism. NEDD8 uniquely contacts covalently linked CUL5, and elicits structural rearrangements that unveil cryptic ARIH2-binding sites. The data reveal how a ubiquitin-like protein induces protein-protein interactions indirectly, through allostery. Allosteric specificity of ubiquitin-like protein modifications may offer opportunities for therapeutic targeting.

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Section: Discussionmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation

et al. 2021

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“…Viral hijacking of host ubiquitin ligases has been described in numerous viral infections. For instance, the RNA virus HIV-1 encodes VPU, VPR, and VIF which each hijack different Cullin−RING−ligase complexes in order to degrade host antiviral proteins and thereby promote infection ( 6 , 7 ). Additionally, the hepatitis B protein HBX hijacks a Cullin-4–containing E3 ubiquitin ligase complex ( 8 ), while adenovirus E4(orf6) hijacks a Cullin-2 complex ( 9 ).…”

mentioning

confidence: 99%

ORF10–Cullin-2–ZYG11B complex is not required for SARS-CoV-2 infection

Mena

Donahue

Vaites

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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In order to understand the transmission and virulence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is necessary to understand the functions of each of the gene products encoded in the viral genome. One feature of the SARS-CoV-2 genome that is not present in related, common coronaviruses is ORF10, a putative 38-amino acid protein-coding gene. Proteomic studies found that ORF10 binds to an E3 ubiquitin ligase containing Cullin-2, Rbx1, Elongin B, Elongin C, and ZYG11B (CRL2ZYG11B). Since CRL2ZYG11B mediates protein degradation, one possible role for ORF10 is to “hijack” CRL2ZYG11B in order to target cellular, antiviral proteins for ubiquitylation and subsequent proteasomal degradation. Here, we investigated whether ORF10 hijacks CRL2ZYG11B or functions in other ways, for example, as an inhibitor or substrate of CRL2ZYG11B. While we confirm the ORF10−ZYG11B interaction and show that the N terminus of ORF10 is critical for it, we find no evidence that ORF10 is functioning to inhibit or hijack CRL2ZYG11B. Furthermore, ZYG11B and its paralog ZER1 are dispensable for SARS-CoV-2 infection in cultured cells. We conclude that the interaction between ORF10 and CRL2ZYG11B is not relevant for SARS-CoV-2 infection in vitro.

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“…Several distinct types of pathogens produce F-box adaptor proteins, which can then act together with host core components in multi-subunit cullin-RING ligases. Such F-box effectors are used by viruses [34,35] as well as by bacterial pathogens such as the plant pathogen Agrobacterium tumefaciens [36], and by L. pneumophila [37]. A recent metagenomics study of 80 Legionella genomes spanning 58 species found that two thirds of the species had either F-box or U-box containing genes [38].…”

Section: Expansion and Diversification Of Ubiquitin Ligases On Both Smentioning

confidence: 99%

Conservation lost: host‐pathogen battles drive diversification and expansion of gene families

Lažetić

Troemel

2020

The FEBS Journal

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One of the strongest drivers in evolution is the struggle to survive a hostpathogen battle. This pressure selects for diversity among the factors directly involved in this battle, including virulence factors deployed by pathogens, their corresponding host targets, and host immune factors. A logical outcome of this diversification is that over time, the sequence of many immune factors will not be evolutionarily conserved across a broad range of species. Thus, while universal sequence conservation is often hailed as the hallmark of the importance of a particular gene, the immune system does not necessarily play by these rules when defending against coevolving pathogens. This loss of sequence conservation is in contrast to many signaling pathways in development and basic cell biology that are not targeted by pathogens. In addition to diversification, another consequence of host-pathogen battles can be an amplification in gene number, thus leading to large gene families that have sequence relatively specific to a particular strain, species, or clade. Here we highlight this general theme across a variety of pathogen virulence factors and host immune factors. We summarize the wide range and number across species of these expanded, lineage-specific host-pathogen factors including ubiquitin ligases, nucleotide-binding leucine-rich repeat receptors, GTPases, and proteins without obvious biochemical function but that nonetheless play key roles in immunity.

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Viral Manipulations of the Cullin-RING Ubiquitin Ligases

Cited by 16 publications

References 88 publications

CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation

CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation

ORF10–Cullin-2–ZYG11B complex is not required for SARS-CoV-2 infection

Conservation lost: host‐pathogen battles drive diversification and expansion of gene families

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