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FAM46C is an IFN stimulated gene that restricts lentiviral particle production by modulating autophagy

ABSTRACT: FAM46C is a multiple myeloma tumour suppressor whose function is only starting to be elucidated. We recently showed that in multiple myeloma cells FAM46C triggers apoptosis by inhibiting autophagy and altering intracellular trafficking and protein secretion. To date, both a physiological characterization of FAM46C role and assessment of FAM46C-induced phenotypes outside of multiple myeloma are lacking. Preliminary reports suggested an involvement of FAM46C with regulation of viral replication but results were scanty and contradictory. Here, we show that FAM46C is an IFN-stimulated gene and that expression in HEK 293T cells of wt FAM46C but not of its most frequently found mutant variants, inhibits replication of both HIV-1 and HIV-1-derived lentiviruses. We demonstrate that this effect does not require transcriptional regulation and does not depend on inhibition of either global or viral-specific translation, but rather mostly relies on FAM46C-induced deregulation of autophagy, a pathway which we show to be required for efficient lentiviral production. These studies not only provide new insights on the physiological role of the FAM46C protein but could also help implementing more efficient antiviral strategies.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: alessandro cuomo

LAB HEAD: Nicola Manfrini

PROVIDER: PXD036818 | Pride | 2023-06-19

REPOSITORIES: Pride

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Project description:The goal of this project is todetermine if natural killer (NK) cells could be able to control HIV replication and reduce or eliminate viral reservoirs leading to HIV cure or a functional cure. Despite thirty years of work and significant progress, HIV infection continues to be an incurable disease. Antiretroviral therapy (ART) has significantly decreased the morbidity and mortality, but lifelong treatment is merely suppressive and does not cure HIV/AIDS. This is because of the existence of a reservoir of viral DNA+ (vDNA+) in cells of the lymphoid tissues with an intact provirus that is thought capable of initiating new rounds of HIV replication (i.e. latency). In addition to this inducible reservoir data suggest ongoing low-level virus replication and persistence in lymphatic tissues of some patients that is related to suboptimal drug levels in these tissues. Strategies are needed that can address both issues. NK cells are innate immune effectors that recognize virally infected targets through a cadre of activating and inhibitory receptors but become dysfunctional in HIV infected people. Strikingly, African green monkeys (AGM) and sooty mangabeys mount a strong control of viral replication in lymph node follicles shortly after the viremia peak that lasts throughout infection. Several mechanisms have been proposed to be implicated in the strong control of viral replication in natural host’s lymph nodes, such as NK cell-mediated control. Indeed, we have recently shown that NK cells could migrate into the b cells follicles in a CXCR5 dependent manner and thus participate to the elimination of viral replication. Thus the purpose of this study is too compare at the transcriptomic level different subset of NK cell isolated from blood and peripheral lymph node of chronically infected AGM to identify a transcriptomic signature which could be linked to an efficient control of SIV replication. This results could then provide a new aproche which could be exploited to generate functional NK cells against HIV in infected patients.

Project description:During HIV-1 infection, there is a massive perturbation of host gene expression, but as yet, genome-wide studies have not identified host genes affecting HIV-1 replication in lymphatic tissue, the primary site of virus-host interactions. In this study, we isolated RNA from the inguinal lymph nodes of 22 HIV-1-infected individuals and utilized a microarray approach to identify host genes critically important for viral replication in lymphatic tissue by examining gene expression associated with viral load. Strikingly, ~95% of the transcripts (558) in this data set (592 transcripts total) were negatively associated with HIV-1 replication. Genes in this subset (1) inhibit cellular activation/proliferation (ex.: TCFL5, SOCS5 and SCOS7, KLF10), (2) promote heterochromatin formation (ex.: HIC2, CREBZF, ZNF148/ZBP-89), (3) increase collagen synthesis (ex.: PLOD2, POSTN, CRTAP), and (4) reduce cellular transcription and translation. Potential anti-HIV-1 restriction factors were also identified (ex.: NR3C1, HNRNPU, PACT). Only ~5% of the transcripts (34) were positively associated with HIV-1 replication. Paradoxically, nearly all these genes function in innate and adaptive immunity, particularly highlighting a heightened interferon system. The predominance of negative correlations as well as the disconnect between host defenses and viral load point to the importance of genes that regulate target cell activation and genes that code for potentially new restriction factors as determinants of viral load rather than conventional host defenses. Total RNA was isolated from the inguinal lymph nodes of 22 HIV-1-infected subjects at different clinical stages (and varying viral loads) and prepared for RNA extraction and hybridization on Affymetrix Human Genome U133 Plus 2.0 microarrays. Replicate arrays were performed for lymph node samples to minimize assay noise and host genes critically important for viral replication in lymphatic tissue were identified by examining gene expression and its association with viral load. Replicates were not performed for samples WB91 and TS35 due to limited amounts of biomaterial.

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FAM46C is an IFN stimulated gene that restricts lentiviral particle production by modulating autophagy

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