bims-nocaut Biomed News
on Non-canonical autophagy
Issue of 2025–11–30
two papers selected by
Quentin Frenger, University of Strasbourg
  1. Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2.
  2. IFN-γ-Driven macrophage responses in the immunity to Mycobacterium tuberculosis and Mycobacterium leprae.
  1. Nat Commun. 2025 Nov 27. 16(1): 10618
    Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2.
    COVID Human Genetic Effort
      The clinical outcome of SARS-CoV-2 infection spans from asymptomatic viral elimination to lethal COVID-19 pneumonia, which is due to type I interferon (IFN) deficiency in at least 15-20% of cases. We report two unrelated male patients with critical COVID-19 who are heterozygous for rare deleterious variants in RB1CC1, encoding the autophagy-related FIP200 protein. Airway epithelial cells genetically deprived of FIP200 or cell lines expressing the RB1CC1/FIP200 patient variants exhibit elevated SARS-CoV-2 replication and impaired autophagic flux. The antiviral function of FIP200 is independent of canonical autophagy and type I IFN, but involves the selective autophagy receptor NDP52. We identify a non-canonical function of FIP200 in a novel lysosomal degradation pathway, in which SARS-CoV-2 virions are targeted to single-membrane compartments for degradation of viral RNA in LC3B-positive acidified vesicles. This pathway is impaired in FIP200-deficient cells and in cells expressing FIP200 patient haplotypes. Collectively, we describe a cell-autonomous anti-SARS-CoV-2 restriction pathway, dependent on FIP200 and NDP52, and independent of canonical autophagy and type I IFN, which can underlie critical COVID-19 pneumonia.
    DOI:  https://doi.org/10.1038/s41467-025-65308-8
  2. Front Cell Infect Microbiol. 2025 ;15 1679691
    IFN-γ-Driven macrophage responses in the immunity to Mycobacterium tuberculosis and Mycobacterium leprae.
    Mohd Imran, Ahmed S Alshrari, Abida Khan, Abdullah R Alzahrani.
      Interferon-gamma (IFN-γ) is a key stimulator of macrophage defense against Mycobacterium tuberculosis (Mtb) and Mycobacterium leprae (M. leprae). Both pathogens adopt measures to circumvent the effects of the immune system, weakening the impact of IFN-γ and enabling them to survive in the cells. This review synthesizes how IFN-γ overdose transacts the JAK/STAT1-IRF1-transmitter to encourage maturation of phagolysosomes, reactive oxygen and nitrogen product generation, LC3-associated phagocytosis (LAP), autophagy, and improved antigen presentation and juxtaposes these pathways in tuberculosis and leprosy. We also explain the mechanisms by which mycobacteria counter this axis, including receptor downregulation, induction of IL-10/SOCS, type I INF antagonism, and the impact of miRNA. Additionally, we assessed the translational application, emphasizing its benefits, potential risks, and sources of variability. Additionally, we discuss biomarker strategies related to IFN-γ activity, such as gene signatures associated with HIF-1 and active IFN-γ measurements, which could aid in selecting patients and tracking their treatment progress. The results show that macrophage-related processes are important for the treatment and diagnosis of TB and leprosy when they occur simultaneously. This highlights the need for safe and effective treatments that focus on the host and balance the protective and harmful effects of IFN-γ.
    Keywords:  CD8+ T cells; Mycobacterium leprae; Mycobacterium tuberculosis; T-helper type 1 cells; interferon-gamma
    DOI:  https://doi.org/10.3389/fcimb.2025.1679691
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