ArticleThe Journal of biological chemistry2008
HIV-1 Nef binds PACS-2 to assemble a multikinase cascade that triggers major histocompatibility complex class I (MHC-I) down-regulation: analysis using short interfering RNA and knock-out mice.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 87 citations in OpenAlex.
- PACS1 syndrome mutation disrupts dynein-mediated cargo transport via HDAC6 and BICD2.Communications biology · 2026Article
- Mechanisms of Immune Evasion in HIV-1: The Role of Virus-Host Protein Interactions.Current issues in molecular biology · 2025Review
- PACS deficiency disrupts Golgi architecture and causes cytokinesis failures and seizure-like phenotype inOpen biology · 2025Article
- Viral manipulation of the HLA class I antigen processing and presentation pathway.Frontiers in immunology · 2025Review
- The PACS-2 protein and trafficking motifs in CCHFV Gn and Gc cytoplasmic domains govern CCHFV assembly.Emerging microbes & infections · 2024Article
- Targeted protein degradation as an antiviral approach.Antiviral research · 2023Article
- Novel role of HIV-1 Nef in regulating the ubiquitination of cellular proteins.Frontiers in cellular and infection microbiology · 2023Article
- Review
- Detection of the HIV-1 Accessory Proteins Nef and Vpu by Flow Cytometry Represents a New Tool to Study Their Functional Interplay within a Single Infected CD4Journal of virology · 2022Article
- Host and Viral Factors Influencing Interplay between the Macrophage and HIV-1.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2019Review
- An Insulin-Responsive Sensor in the SIRT1 Disordered Region Binds DBC1 and PACS-2 to Control Enzyme Activity.Molecular cell · 2018Article
- Article
- HIV-1 Nef Antagonizes SERINC5 Restriction by Downregulation of SERINC5 via the Endosome/Lysosome System.Journal of virology · 2018Article
- Modeling the evolution of SIV sooty mangabey progenitor virus towards HIV-2 using humanized mice.Virology · 2017Article
- HIV-I Nef inhibitors: a novel class of HIV-specific immune adjuvants in support of a cure.AIDS research and therapy · 2017Review
- Caught in the act - protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease.Journal of cell science · 2017Review
- Where in the Cell Are You? Probing HIV-1 Host Interactions through Advanced Imaging Techniques.Viruses · 2016Review
- PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage.Cell death and differentiation · 2016Article
- Remodeling of the Host Cell Plasma Membrane by HIV-1 Nef and Vpu: A Strategy to Ensure Viral Fitness and Persistence.Viruses · 2016Review
- Improving HIV proteome annotation: new features of BioAfrica HIV Proteomics Resource.Database : the journal of biological databases and curation · 2016Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Human immunodeficiency virus, type 1, negative factor (Nef) initiates down-regulation of cell-surface major histocompatibility complex-I (MHC-I) by assembling an Src family kinase (SFK)-ZAP70/Syk-phosphoinositide 3-kinase (PI3K) cascade through the sequential actions of two sites, Nef EEEE(65) and PXXP(75). The internalized MHC-I molecules are then sequestered in endosomal compartments by a process requiring Nef Met(20). How Nef assembles the multikinase cascade to trigger the MHC-I down-regulation pathway is unknown. Here we report that EEEE(65)-dependent binding to the sorting protein PACS-2 targets Nef to the paranuclear region, enabling PXXP(75) to bind and activate a trans-Golgi network (TGN)-localized SFK. This SFK then phosphorylates ZAP-70 to recruit class I PI3K by interaction with the p85 C-terminal Src homology 2 domain. Using splenocytes and embryonic fibroblasts from PACS-2(-/-) mice, we confirm genetically that Nef requires PACS-2 to localize to the paranuclear region and assemble the multikinase cascade. Moreover, genetic loss of PACS-2 or inhibition of class I PI3K prevents Nef-mediated MHC-I down-regulation, demonstrating that short interfering RNA knockdown of PACS-2 phenocopies the gene knock-out. This PACS-2-dependent targeting pathway is not restricted to Nef, because PACS-2 is also required for trafficking of an endocytosed cation-independent mannose 6-phosphate receptor reporter from early endosomes to the TGN. Together, these results demonstrate PACS-2 is required for Nef action and sorting of itinerant membrane cargo in the TGN/endosomal system.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.