scholarly journals RNA-controlled nucleocytoplasmic shuttling of mRNA decay factors regulates mRNA synthesis and initiates a novel mRNA decay pathway

2021 ◽  
Author(s):  
Shiladitya Chattopadhyay ◽  
Jose Garcia-Martinez ◽  
Gal Haimovich ◽  
Aya Khwaja ◽  
Oren Barkai ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Mrna Decay ◽  
Environmental Changes ◽  
Mrna Level ◽  
Mrna Synthesis ◽  
Nucleocytoplasmic Shuttling ◽  
Decay Factor ◽  
Environmental Fluctuations ◽  
Cellular Mrnas ◽  
Nuclear Localization Sequences

AbstractmRNA level is controlled by factors that mediate both mRNA synthesis and decay, including the exonuclease Xrn1 - a major mRNA synthesis and decay factor. Here we show that nucleocytoplasmic shuttling of Xrn1 and of some of its associated mRNA decay factors plays a key role in determining both mRNA synthesis and decay. Shuttling is regulated by RNA-controlled binding of the karyopherin Kap120 to two nuclear localization sequences (NLSs) in Xrn1. The decaying RNA binds and masks NLS1, establishing a link between mRNA decay and Xrn1 shuttling. Mutations in the two NLSs, which prevent Xrn1 import, compromise transcription and, unexpectedly, also the cytoplasmic decay of ∼50% of the cellular mRNAs - comparably to Xrn1 deletion. These findings uncover a cytoplasmic mRNA decay pathway that begins in the nucleus. Interestingly, Xrn1 shuttling is required for proper adaptation to environmental changes, in particular to ever changing environmental fluctuations.

The C-terminal domain of Salmonid Alphavirus nonstructural protein 2 (nsP2) is essential and sufficient to block RIG-I pathway induction and interferon-mediated antiviral response.

2021 ◽  
Author(s):  
Raphaël Jami ◽  
Emilie Mérour ◽  
Julie Bernard ◽  
Annie Lamoureux ◽  
Jean K. Millet ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune Response ◽  
Nuclear Localization ◽  
Innate Immune ◽  
Type I ◽  
Annual Growth Rate ◽  
Structural Protein ◽  
Terminal Domain ◽  
Nuclear Localization Sequences

Salmonid alphavirus (SAV) is an atypical alphavirus, which has a considerable impact on salmon and trout farms. Unlike other alphaviruses such as the chikungunya virus, SAV is transmitted without an arthropod vector, and does not cause cell shut-off during infection. The mechanisms by which SAV escapes the host immune system remain unknown. By studying the role of SAV proteins on the RIG-I signaling cascade, the first line of defense of the immune system during infection, we demonstrated that non-structural protein 2 (nsP2) effectively blocks the induction of type I interferon (IFN). This inhibition, independent of the protease activity carried by nsP2, occurs downstream of IRF3 which is the transcription factor allowing the activation of the IFN promoter and its expression. The inhibitory effect of nsP2 on the RIG-I pathway depends on the localization of nsP2 in the host cell nucleus which is linked to two nuclear localization sequences (NLS) located in its C-terminal part. The C-terminal domain of nsP2 by itself is sufficient and necessary to block IFN induction. Mutation of the NLS of nsP2 is deleterious to the virus. Finally, nsP2 does not interact with IRF3, indicating that its action is possible through a targeted interaction within discrete areas of chromatin, as suggested by its punctate distribution observed in the nucleus. These results therefore demonstrate a major role for nsP2 in the control by SAV of the host cell’s innate immune response. Importance The global consumption of fish continues to rise and the future demand cannot be met by capture fisheries alone due to limited stocks of wild fish. Aquaculture is currently the world’s fastest growing food production sector with an annual growth rate of 6-8 %. Recurrent outbreaks of SAV result in significant economic losses with serious environmental consequences on wild stocks. While the clinical and pathological signs of SAV infection are fairly well known, the molecular mechanisms involved are poorly described. In the present study, we focus on the non-structural protein nsP2 and characterize a specific domain containing nuclear localization sequences that are critical for the inhibition of the host innate immune response mediated by the RIG-I pathway.

scholarly journals Mutations in Tap Uncouple RNA Export Activity from Translocation through the Nuclear Pore Complex

2006 ◽  
Vol 17 (2) ◽  
pp. 931-943 ◽  
Author(s):  
Lyne Lévesque ◽  
Yeou-Cherng Bor ◽  
Leah H. Matzat ◽  
Li Jin ◽  
Stephen Berberoglu ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Point Mutations ◽  
Nuclear Pore ◽  
Nucleocytoplasmic Shuttling ◽  
Transport Receptors ◽  
Cellular Mrnas ◽  
Rna Export ◽  
Rna Complex ◽  
Transport Receptor

Interactions between transport receptors and phenylalanine-glycine (FG) repeats on nucleoporins drive the translocation of receptor-cargo complexes through nuclear pores. Tap, a transport receptor that mediates nuclear export of cellular mRNAs, contains a UBA-like and NTF2-like folds that can associate directly with FG repeats. In addition, two nuclear export sequences (NESs) within the NTF2-like region can also interact with nucleoporins. The Tap-RNA complex was shown to bind to three nucleoporins, Nup98, p62, and RanBP2, and these interactions were enhanced by Nxt1. Mutations in the Tap-UBA region abolished interactions with all three nucleoporins, whereas the effect of point mutations within the NTF2-like domain of Tap known to disrupt Nxt1 binding or nucleoporin binding were nucleoporin dependent. A mutation in any of these Tap domains was sufficient to reduce RNA export but was not sufficient to disrupt Tap interaction with the NPC in vivo or its nucleocytoplasmic shuttling. However, shuttling activity was reduced or abolished by combined mutations within the UBA and either the Nxt1-binding domain or NESs. These data suggest that Tap requires both the UBA- and NTF2-like domains to mediate the export of RNA cargo, but can move through the pores independently of these domains when free of RNA cargo.

scholarly journals Differential restriction patterns of mRNA decay factor AUF1 during picornavirus infections

2014 ◽  
Vol 95 (7) ◽  
pp. 1488-1492 ◽  
Author(s):  
Andrea L. Cathcart ◽  
Bert L. Semler
Keyword(s):  
Mrna Decay ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Encephalomyocarditis Virus ◽  
Restriction Factor ◽  
Host Proteins ◽  
Specific Host ◽  
Decay Factor ◽  
Cellular Environment ◽  
Binding Factor

During infection by picornaviruses, the cellular environment is modified to favour virus replication. This includes the modification of specific host proteins, including the recently discovered viral proteinase cleavage of mRNA decay factor AU-rich binding factor 1 (AUF1). This cellular RNA-binding protein was shown previously to act as a restriction factor during poliovirus, rhinovirus and coxsackievirus infection. During infection by these viruses, AUF1 relocalizes to the cytoplasm and is cleaved by the viral 3C/3CD proteinase. In this study, we demonstrated that replication of encephalomyocarditis virus (EMCV), a picornavirus belonging to the genus Cardiovirus, is AUF1 independent. During EMCV infection, AUF1 relocalized to the cytoplasm; however, unlike what is seen during enterovirus infections, AUF1 was not cleaved to detectable levels, even at late times after infection. This suggests that AUF1 does not act broadly as an inhibitor of picornavirus infections but may instead act as a selective restriction factor targeting members of the genus Enterovirus.

scholarly journals Nuclear Localization Sequences in Cytomegalovirus Capsid Assembly Proteins (UL80 Proteins) Are Required for Virus Production: Inactivating NLS1, NLS2, or Both Affects Replication to Strikingly Different Extents

2008 ◽  
Vol 82 (11) ◽  
pp. 5381-5389 ◽  
Author(s):  
Nang L. Nguyen ◽  
Amy N. Loveland ◽  
Wade Gibson
Keyword(s):  
Nuclear Localization ◽  
Infectious Virus ◽  
Nuclear Translocation ◽  
Virus Production ◽  
Wild Type Virus ◽  
Capsid Assembly ◽  
Scaffolding Proteins ◽  
Hcmv Replication ◽  
Protease Precursor ◽  
Nuclear Localization Sequences

ABSTRACT Scaffolding proteins of spherical prokaryotic and eukaryotic viruses have critical roles in capsid assembly. The primary scaffolding components of cytomegalovirus, called the assembly protein precursor (pAP, pUL80.5) and the maturational protease precursor (pPR, pUL80a), contain two nuclear localization sequences (NLS1 and NLS2), at least one of which is required in coexpression experiments to translocate the major capsid protein (MCP, pUL85) into the nucleus. In the work reported here, we have mutated NLS1 and NLS2, individually or together, in human cytomegalovirus (HCMV, strain AD169) bacmid-derived viruses to test their effects on virus replication. Consistent with results from earlier transfection/coexpression experiments, both single-mutant bacmids gave rise to infectious virus but the double mutant did not. In comparisons with the wild-type virus, both mutants showed slower cell-to-cell spread; decreased yields of infectious virus (3-fold lower for NLS1− and 140-fold lower for NLS2−); reduced efficiency of pAP, pPR, and MCP nuclear translocation (sixfold lower for NLS1− and eightfold lower for NLS2−); increased amounts of a 120-kDa MCP fragment; and reduced numbers of intranuclear capsids. All effects were more severe for the NLS2− mutant than the NLS1− mutant, and a distinguishing feature of cells infected with the NLS2− mutant was the accumulation of large, UL80 protein-containing structures within the nucleus. We conclude that these NLS assist in the nuclear translocation of MCP during HCMV replication and that NLS2, which is unique to the betaherpesvirus UL80 homologs, may have additional involvements during replication.

The Arabidopsis thaliana mRNA decay factor PAT1 functions in osmotic stress responses and decaps ABA‐responsive genes

FEBS Letters ◽  
2020 ◽  
Author(s):  
Zhangli Zuo ◽  
Milena Edna Roux ◽  
Holger Páll Sæmundsson ◽  
Maren Müller ◽  
Sergi Munne Bosch ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Osmotic Stress ◽  
Stress Responses ◽  
Mrna Decay ◽  
Decay Factor

scholarly journals The mRNA Decay Factor CAR-1/LSM14 Regulates Axon Regeneration via Mitochondrial Calcium Dynamics

2020 ◽  
Vol 30 (5) ◽  
pp. 865-876.e7 ◽  
Author(s):  
Ngang Heok Tang ◽  
Kyung Won Kim ◽  
Suhong Xu ◽  
Stephen M. Blazie ◽  
Brian A. Yee ◽  
...  
Keyword(s):  
Mrna Decay ◽  
Axon Regeneration ◽  
Mitochondrial Calcium ◽  
Calcium Dynamics ◽  
Decay Factor

scholarly journals REST/NRSF-Interacting LIM Domain Protein, a Putative Nuclear Translocation Receptor

2003 ◽  
Vol 23 (24) ◽  
pp. 9025-9031 ◽  
Author(s):  
Masahito Shimojo ◽  
Louis B. Hersh
Keyword(s):  
Nuclear Localization ◽  
Nuclear Translocation ◽  
Protein A ◽  
Lim Domain ◽  
Nuclear Targeting ◽  
Lim Domains ◽  
Lim Domain Protein ◽  
Domain Protein ◽  
Nuclear Localization Sequences ◽  
Novel Protein

ABSTRACT The transcriptional repressor REST/NRSF (RE-1 silencing transcription factor/neuron-restrictive silencer factor) and the transcriptional regulator REST4 share an N-terminal zinc finger domain structure involved in nuclear targeting. Using this domain as bait in a yeast two-hybrid screen, a novel protein that contains three LIM domains, putative nuclear localization sequences, protein kinase A phosphorylation sites, and a CAAX prenylation motif was isolated. This protein, which is localized around the nucleus, is involved in determining the nuclear localization of REST4 and REST/NRSF. We propose the name RILP, for REST/NRSF-interacting LIM domain protein, to label this novel protein. RILP appears to serve as a nuclear receptor for REST/NRSF, REST4, and possibly other transcription factors.

Sign in / Sign up

Export Citation Format

Share Document