Cellular and Molecular Life Sciences最新文献

Both Human immunodeficiency virus (HIV) and Epstein-Barr Virus (EBV) are associated with an increased risk of malignancies. HIV infection is associated with EBV reactivation and an increase in EBV viral loads in saliva and blood, and people living with HIV frequently develop EBV-associated B-cell malignancies. In this study, we aimed to investigate the involvement of HIV-1 and EBV co-existence in the development of B-cell malignancies. To do so, we focused our attention on the two viral transcriptional activators (HIV-1 Tat and EBV Zta) and analyzed their possible interaction since they both have cell-penetration domains and can be found simultaneously in the blood or cells of people living with HIV. We investigated the interaction of Tat and Zta using co-immunoprecipitation, in vitro binding, YFP reconstitution assay and FRET. We found that they bind each other in human B cells and blood serum. Tat and Zta interaction was also observed in a serum sample from one HIV-positive individual. YFP reconstitution demonstrated that this interaction occurred predominantly in the nucleus, indicating that it might affect the host genome. We further analyzed the effects of Tat and Zta on primary and EBV-transformed human B cells by RNA-sequencing and found that the combined Tat and Zta action in B cells differed from a single action of the two proteins. A subset of genes, activated by Tat or Zta alone, that trigger an immune response and antigen presentation in B cells, remained unchanged when the two proteins were combined. B cells, treated or transfected with Tat and Zta, exhibited a substantial decrease in HLA-ABC (MHC class I) expression, a critical component of the antigen processing and presentation pathway. Our findings suggest that the reduction of total HLA-ABC levels in B cells upon Tat and Zta interaction might be linked to HLA-ABC proteasomal degradation. Furthermore, HLA-ABC downregulation induced by Tat and Zta interaction conferred protection against cytotoxic T cell recognition of EBV-infected B cells. To conclude, we demonstrated for the first time that HIV-1 Tat and EBV Zta interacted directly in B cells and blood serum; this interaction can be found in people with HIV. This interaction brings about immune evasion of EBV-infected or transformed B cells.

Spinal cord injury (SCI) initiates a complex neuroimmune cascade, where the interplay between damaged neural circuits and the inflammatory response critically determines clinical outcomes. A pivotal but poorly understood aspect of this interplay is the aberrant regeneration of CGRP⁺ sensory nerve fibers and their dynamic communication with immune cells. This review systematically delineates the spatiotemporal remodeling of CGRP⁺ fibers post-SCI and elucidates their time-dependent regulation of macrophage polarization. We synthesize emerging evidence on how CGRP signaling, through receptors like CLR/RAMP1 and downstream pathways (e.g., cAMP/PKA, MAPK), fine-tunes the macrophage polarization continuum across different injury phases, thereby influencing the neuroimmune microenvironment. Furthermore, we explore the synergistic actions of CGRP with other neuropeptides and the cross-regulation with key inflammatory signaling hubs, such as NF-κB and STAT3. By integrating these multifaceted interactions, this review not only provides a novel perspective on the neuroimmune pathogenesis of SCI but also highlights the therapeutic potential of targeting the CGRP pathway to foster neural repair and restore immune homeostasis.

Pathogenic variants in GRIN2B, encoding the NMDA receptor (NMDAR) GluN2B subunit, are linked to intellectual disability (ID) and related neurodevelopmental disorders. While most disease-associated variants are missense, protein-truncating variants (PTVs) may cause haploinsufficiency with less severe phenotypes. Here, we characterize a knock-in mouse model carrying the GluN2B-L825Ffs*15 PTV (Grin2b^+/Δ). Proteomic analysis revealed markedly reduced full-length GluN2B protein and no detectable truncated GluN2B, accompanied by a small compensatory increase in GluN2A. Electrophysiology in hippocampal neurons demonstrated reduced NMDA-induced currents, diminished ifenprodil sensitivity, and accelerated NMDAR-mediated EPSC deactivation, consistent with a shift toward GluN2A-containing receptors. AMPAR-mEPSC amplitudes were increased, indicating altered excitatory synaptic function. Behaviorally, Grin2b^+/Δ mice exhibited hypoactivity, increased anxiety in males, and impaired sensorimotor gating in both sexes, while learning, memory, and social behaviors remained largely intact. These results demonstrate that a monoallelic GluN2B PTV alters NMDAR subunit composition and function, producing moderate behavioral effects, and provide insight into mechanisms underlying GRIN2B-associated ID.