The Role of Promyelocytic Leukemia Nuclear Bodies During HPV Infection

Guion, Lucile G. M.; Sapp, Martin

doi:10.3389/fcimb.2020.00035

Cited by 23 publications

(26 citation statements)

References 94 publications

(126 reference statements)

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“…Previous studies with HeLa cells reported that recombinant RGS14 translocates from the cytosol to the nucleus following mild heat stress (26). There, RGS14 localized to promyelocytic leukemia (PML) bodies, which have been implicated in cellular processes such as apoptosis, transcriptional regulation, DNA repair and replication (50). However, we have not observed native RGS14 localization at PML bodies in mouse hippocampal neurons, monkey striatal neurons (31), or rat B35 neuroblastoma cells (27), suggesting RGS14 PML body localization may be limited to unnatural host or non-neuronal cells.…”

Section: Discussionmentioning

confidence: 99%

Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons

Squires

Gerber

Tillman³

et al. 2020

Preprint

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The human genome contains vast genetic diversity in the form of naturally occurring coding variants, yet the impact of these variants on protein function and physiology is poorly understood. RGS14 is a multifunctional signaling protein that suppresses synaptic plasticity in dendritic spines of hippocampal neurons. RGS14 also is a nucleocytoplasmic shuttling protein, suggesting that balanced nuclear import/export and dendritic spine localization are essential for RGS14 functions. We identified genetic variants L505R (LR) and R507Q (RQ) located within the nuclear export sequence (NES) of human RGS14. Here we report that RGS14 carrying LR or RQ profoundly impacts protein functions in hippocampal neurons and brain. Following nuclear import, RGS14 nuclear export is regulated by Exportin 1 (XPO1/CRM1). Remarkably, LR and RQ variants disrupt RGS14 binding to Gαi1-GDP and XPO1, nucleocytoplasmic equilibrium, and capacity to inhibit LTP. Variant LR accumulates irreversibly in the nucleus, preventing RGS14 binding to G proteins, localization to dendritic spines, and inhibitory actions on LTP induction, while variant RQ exhibits a mixed phenotype. When introduced into mice by CRISPR/Cas9, RGS14-LR protein expression was detected predominantly in the nuclei of neurons within hippocampus, central amygdala, piriform cortex, and striatum, brain regions associated with learning and synaptic plasticity. Whereas mice completely lacking RGS14 exhibit enhanced spatial learning, mice carrying variant LR exhibit normal spatial learning, suggesting that RGS14 may have distinct functions in the nucleus independent from those in dendrites and spines. These findings show that naturally occurring genetic variants can profoundly alter normal protein function, impacting physiology in unexpected ways.

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Section: Discussionmentioning

confidence: 99%

Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons

Squires

Gerber

Tillman³

et al. 2020

Preprint

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“…The initiation of VRCs of DNA viruses occurs at sites near PML-nuclear bodies. Human papillomavirus (HPV) infection requires the presence of PML protein suggesting that PML bodies are essential to establish infection [ 133 , 134 ]. However, Sp100 and DAXX, which act as transcriptional repressors, restrict viral gene expression in ADV [ 135 ], HPV [ 136 ], HSV-1 [ 137 ], and HCMV [ 138 ] infections.…”

Section: Interplay Between Viral Ibs and Innate Immunitymentioning

confidence: 99%

Negri bodies and other virus membrane-less replication compartments

Nevers

Albertini

Lagaudrière-Gesbert

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Viruses reshape the organization of the cell interior to achieve different steps of their cellular cycle. Particularly, viral replication and assembly often take place in viral factories where specific viral and cellular proteins as well as nucleic acids concentrate. Viral factories can be either membrane-delimited or devoid of any cellular membranes. In the latter case, they are referred as membrane-less replication compartments. The most emblematic ones are the Negri bodies, which are inclusion bodies that constitute the hallmark of rabies virus infection. Interestingly, Negri bodies and several other viral replication compartments have been shown to arise from a liquid-liquid phase separation process and, thus, constitute a new class of liquid organelles. This is a paradigm shift in the field of virus replication. Here, we review the different aspects of membrane-less virus replication compartments with a focus on the Mononegavirales order and discuss their interactions with the host cell machineries and the cytoskeleton. We particularly examine the interplay between viral factories and the cellular innate immune response, of which several components also form membrane-less condensates in infected cells.

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“…HCMV IE1 binds to PML in a complex with ISGF3 to impede IFN-I signaling [ 90 ]. In contrast, HPV requires PML nuclear bodies to establish infection [ 214 ]. Other examples for viral targeting PML include that EMCV 3C protease promotes PML degradation [ 215 ] and that the rabies virus phosphoprotein P and its truncated mutants cause the redistribution of PML-NBs into the cytoplasm [ 216 ].…”

Section: Viral Strategies To Subvert Trim-mediated Ifn-i Regulatormentioning

confidence: 99%

TRIMming Type I Interferon-Mediated Innate Immune Response in Antiviral and Antitumor Defense

Ning

2021

Viruses

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The tripartite motif (TRIM) family comprises at least 80 members in humans, with most having ubiquitin or SUMO E3 ligase activity conferred by their N-terminal RING domain. TRIMs regulate a wide range of processes in ubiquitination- or sumoylation-dependent manners in most cases, and fewer as adaptors. Their roles in the regulation of viral infections, autophagy, cell cycle progression, DNA damage and other stress responses, and carcinogenesis are being increasingly appreciated, and their E3 ligase activities are attractive targets for developing specific immunotherapeutic strategies for immune diseases and cancers. Given their importance in antiviral immune response, viruses have evolved sophisticated immune escape strategies to subvert TRIM-mediated mechanisms. In this review, we focus on their regulation of IFN-I-mediated innate immune response, which plays key roles in antiviral and antitumor defense.

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The Role of Promyelocytic Leukemia Nuclear Bodies During HPV Infection

Cited by 23 publications

References 94 publications

Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons

Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons

Negri bodies and other virus membrane-less replication compartments

TRIMming Type I Interferon-Mediated Innate Immune Response in Antiviral and Antitumor Defense

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