It is uncertain whether nonenveloped karyophilic virus particles may actively traffic from the nucleus outward. The unordered amino-terminal domain of the VP2 major structural protein (2Nt) of the icosahedral parvovirus minute virus of mice (MVM) is internal in empty capsids, but it is exposed outside of the shell through the fivefold axis of symmetry in virions with an encapsidated single-stranded DNA genome, as well as in empty capsids subjected to a heat-induced structural transition. In productive infections of transformed and normal fibroblasts, mature MVM virions were found to efficiently exit from the nucleus prior to cell lysis, in contrast to the extended nuclear accumulation of empty capsids. Newly formed mutant viruses lacking the three phosphorylated serine residues of 2Nt were hampered in their exit from the human transformed NB324K nucleus, in correspondence with the capacity of 2Nt to drive microinjected phosphorylated heated capsids out of the nucleus. However, in normal mouse A9 fibroblasts, in which the MVM capsid was phosphorylated at similar sites but with a much lower rate, the nuclear exit of virions and microinjected capsids harboring exposed 2Nt required the infection process and was highly sensitive to inhibition of the exportin CRM1 in the absence of a demonstrable interaction. Thus, the MVM virion exits the nucleus by accessing nonconventional export pathways relying on cell physiology that can be intensified by infection but in which the exposure of 2Nt remains essential for transport. The flexible 2Nt nuclear transport signal may illustrate a common structural solution used by nonenveloped spherical viruses to propagate in undamaged host tissues.Many eukaryotic viruses invade the nucleus to access the cellular replication and transcription machineries that are necessary for their multiplication. A central process in the life cycle of karyophilic viruses is the passage of viral macromolecules across the nuclear pore complex (NPC) (13, 58), a supramolecular structure regulating nuclear-cytoplasmic transport. For nuclear invasion, viruses use the cellular classical and nonclassical protein import routes (73), which are directed in the classical pathway by basic nuclear localization signals (NLS) (26, 57) recognizing soluble transport receptors of the importin family and other cofactors (31, 72; for a review, see reference 38). The exposure of an NLS to interact with importins (27, 44) and the size of the nuclear viruses, which are generally larger than the 25-to 39-nm functional diameter of the NPC central channel for nondeformable cargo (14, 49), imposes in most cases a drastic conformational change or a complete disassembly of the virus structure for genome delivery into the nucleus (53, 66; for a review, see reference 12).Late in infection, viruses maturing within the nucleus must egress from the infected cell, and it is generally believed that membrane disorganization and cellular lysis follow the nuclear accumulation of virus particles. Nevertheless, the large enveloped herpesvirus...
Modulation of macrophage survival is a critical factor in the resolution of inflammatory responses. Exposure to LPS protects innate immune cells against apoptosis, although the precise pathways responsible for prolongation of macrophage survival remain to be fully established. The goal of this study was to characterize the mechanism of TLR4-mediated survival of murine bone marrow-derived macrophages upon M-CSF withdrawal in more detail. Using a combination of knockout mice and pharmacological inhibitors allowed us to show that TLR4 and TLR2 stimulation promotes long-term survival of macrophages in a MyD88-, PI3K-, ERK-, and NF-κB-dependent manner. LPS-induced long-term, but not short-term, survival requires autocrine signaling via TNF-α and is facilitated by a general cytoprotective program, similar to that mediated by M-CSF. TLR4-mediated macrophage survival is accompanied by a remarkable up-regulation of specific cell surface markers, suggesting that LPS stimulation leads to the differentiation of macrophages toward a mixed macrophage/dendritic cell-like phenotype.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.