Regulated Nuclear Trafficking of rpL10A Mediated by NIK1 Represents a Defense Strategy of Plant Cells against Virus

The NSP-interacting kinase (NIK) receptor-mediated defense pathway has been identified recently as a virulence target of the geminivirus nuclear shuttle protein (NSP). However, the NIK1–NSP interaction does not fit into the elicitor–receptor model of resistance, and hence the molecular mechanism that links this antiviral response to receptor activation remains obscure. Here, we identified a ribosomal protein, rpL10A, as a specific partner and substrate of NIK1 that functions as an immediate downstream effector of NIK1-mediated response. Phosphorylation of cytosolic rpL10A by NIK1 redirects the protein to the nucleus where it may act to modulate viral infection. While ectopic expression of normal NIK1 or a hyperactive NIK1 mutant promotes the accumulation of phosphorylated rpL10A within the nuclei, an inactive NIK1 mutant fails to redirect the protein to the nuclei of co-transfected cells. Likewise, a mutant rpL10A defective for NIK1 phosphorylation is not redirected to the nucleus. Furthermore, loss of rpL10A function enhances susceptibility to geminivirus infection, resembling the phenotype of nik1 null alleles. We also provide evidence that geminivirus infection directly interferes with NIK1-mediated nuclear relocalization of rpL10A as a counterdefensive measure. However, the NIK1-mediated defense signaling neither activates RNA silencing nor promotes a hypersensitive response but inhibits plant growth and development. Although the virulence function of the particular geminivirus NSP studied here overcomes this layer of defense in Arabidopsis, the NIK1-mediated signaling response may be involved in restricting the host range of other viruses

Reduction of Qm Protein Expression Correlates with Tumor Grade in Prostatic Adenocarcinoma

The QM protein is a transcription cofactor inhibiting the activity of AP-1 transcription factors and is also a ribosomal protein participating in protein synthesis. While protein synthesis is known to be increased in many cancers, inhibition of AP-1 activity presumably suppresses development and growth of sex-hormone-regulated tumor cells. The present study is the first report on immunohistochemical data of QM in human prostatic tissues. Paraffin sections of human prostate cancer samples were immunohistochemically stained for QM. The staining scores were analyzed with the clinicopathologic data of the patients. QM protein expression was found in all normal prostate glands adjacent to prostate cancer and in various intraepithelial neoplasia ( PIN). In prostate cancer, the staining intensity and stained areas were decreased, compared to the normal glands and PIN lesions; in high-grade tumors only some patches of tumor cells showed positivity. Intense (3+) staining was mostly observed in the Gleason grade three areas (48%) compared to grade 4 and 5 areas (22%), although both low and high-grade tumors showed similar percentages of weakly stained areas. Moreover, staining in prostatic adenocarcinoma was often topographically patchy and varied from negative or weak (1+) to intense (3+). There was an inverse correlation from normal to low-grade tumors and then to high-grade tumors. However, in high-grade tumors, the positive areas were mostly confined to peripheral aspects of tumors and were particularly strong in foci of perineural invasion. This preliminary study suggests that decreased QM expression may be associated with early development of prostate cancer, but later a high level of QM may facilitate progression of the tumors to a more aggressive phenotype.WoSScopu

Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists

CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human Class A G protein-coupled receptors (GPCRs). CCR2 is expressed on monocytes, immature dendritic cells and T cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2(1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases(2) including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer(3). These disease associations have motivated numerous preclinical studies and clinical trials(4) (see ClinicalTrials.gov) in search of therapies that target the CCR2:chemokine axis. To aid drug discovery efforts(5), we solved a structure of CCR2 in a ternary complex with an orthosteric (BMS-681(6)) and allosteric (CCR2-RA-[R](7)) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in Class A GPCRs to date; this site spatially overlaps the G protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive GPCR structures solved to date. Like other protein:protein interactions, receptor:chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome drug design obstacles

NIK1-mediated translation suppression functions as a plant antiviral immunity mechanism

Plants and plant pathogens are subject to continuous co-evolutionary pressure for dominance, and the outcomes of these interactions can substantially impact agriculture and food security(1–3). In virus– plant interactions, one of the major mechanisms for plant antiviral immunity relies on RNA silencing, which is often suppressed by co-evolving virus suppressors, thus enhancing viral pathogenicity in susceptible hosts(1). In addition, plants use the nucleotide-binding and leucine-rich repeat (NB-LRR) domain-containing resistance proteins, which recognize viral effectors to activate effector-triggered immunity in a defence mechanism similar to that employed in non-viral infections(2,3). Unlike most eukaryotic organisms, plants are not known to activate mechanisms of host global translation suppression to fight viruses(1,2). Here we demonstrate in Arabidopsis that the constitutive activation of NIK1, a leucine-rich repeat receptor-like kinase (LRR-RLK) identified as a virulence target of the begomovirus nuclear shuttle protein (NSP)(4–6), leads to global translation suppression and translocation of the downstream component RPL10 to the nucleus, where it interacts with a newly identified MYB-like protein, L10-INTERACTING MYB DOMAIN-CONTAINING PROTEIN (LIMYB), to downregulate translational machinery genes fully. LIMYB overexpression represses ribosomal protein genes at the transcriptional level, resulting in protein synthesis inhibition, decreased viral messenger RNA association with polysome fractions and enhanced tolerance to begomovirus. By contrast, the loss of LIMYB function releases the repression of translation-related genes and increases susceptibility to virus infection. Therefore, LIMYB links immune receptor LRR-RLK activation to global translation suppression as an antiviral immunity strategy in plants