bims-nocaut 2025-09-07 papers

Issue of 2025–09–07
four papers selected by
Quentin Frenger, University of Strasbourg

Autophagy Rep. 2025 ;4(1): 2542904

Autophagy is an evolutionarily conserved cellular process that is prominent during bacterial infections. In this review article, we discuss how direct pathogen clearance via xenophagy and regulation of inflammatory products represent dual functions of autophagy that coordinate an effective antimicrobial response. We detail the molecular mechanisms of xenophagy, including signals that indicate the presence of an intracellular pathogen and autophagy receptor-mediated cargo targeting, while highlighting pathogen counterstrategies, such as bacterial effector proteins that inhibit autophagy initiation or exploit autophagic membranes for replication. Pathways that are related to autophagy, including LC3-associated phagocytosis (LAP) and conjugation of ATG8 to single membranes (CASM), are expanding the role of autophagy in antimicrobial defense beyond traditional double-membrane autophagosomes. Examination of Crohn disease-associated genes links impaired autophagy to inflammation and defective bacterial handling. We propose emerging concepts, such as effector-triggered immunity, where autophagy inhibition by pathogens triggers inflammatory defenses and discusses the therapeutic potential of modulating autophagy in infectious and inflammatory diseases.

Keywords: Autophagy; CASM; Crohn disease; LC3 associated phagocytosis; bacteria; xenophagy

DOI: https://doi.org/10.1080/27694127.2025.2542904

J Cell Biol. 2025 Oct 06. pii: e202307079. [Epub ahead of print]224(10):

ATG conjugation-dependent/independent mechanisms underlie lysosomal stress-induced TFEB regulation.

Shiori Akayama, Takayuki Shima, Tatsuya Kaminishi, Mengying Cui, Jlenia Monfregola, Kohei Nishino, Andrea Ballabio, Hidetaka Kosako, Tamotsu Yoshimori, Shuhei Nakamura.

TFEB, a master regulator of autophagy and lysosomal biogenesis, is activated by several cellular stresses including lysosomal damage, but its underlying mechanism is unclear. TFEB activation during lysosomal damage depends on the ATG conjugation system, which mediates lipidation of ATG8 proteins. Here, we newly identify ATG conjugation-independent TFEB regulation that precedes ATG conjugation-dependent regulation, designated Modes I and II, respectively. We reveal unique regulators of TFEB in each mode: APEX1 in Mode I and CCT7 and/or TRIP6 in Mode II. APEX1 interacts with TFEB independently of the ATG conjugation system, and is required for TFEB stability, while both CCT7 and TRIP6 accumulate on lysosomes during lysosomal damage, and interact with TFEB mainly in ATG conjugation system-deficient cells, presumably blocking TFEB activation. TFEB activation by several other stresses also involves either Mode I or Mode II. Our results pave the way for a unified understanding of TFEB regulatory mechanisms from the perspective of the ATG conjugation system under a variety of cellular stresses.

DOI: https://doi.org/10.1083/jcb.202307079

FEMS Microbiol Rev. 2025 Sep 02. pii: fuaf040. [Epub ahead of print]

Exploring the multilayered response of TB bacterium Mycobacterial tuberculosis to lysosomal injury.

Mohd Shariq, Javaid Ahmad Sheikh, Asrar Ahmad Malik, Anwar Alam, Peter N Monk, Seyed E Hasnain, Nasreen Z Ehtesham.

Mtb subverts host immune surveillance by damaging phagolysosomal membranes, exploiting them as replication niches. In response, host cells initiate a coordinated LDR, integrating membrane repair, selective autophagy, and de novo biogenesis. This review delineates a systems-level model of lysosomal quality control governed by three critical regulatory axes: LGALS3/8/9, TRIM E3 ubiquitin ligases, and the AMPK-TFEB signaling pathway. LGALSs detect exposed glycans on ruptured membranes, triggering ESCRT-mediated repair and recruiting ARs. TRIM proteins mediate context-specific ubiquitination, enhancing cargo selection and facilitating transcriptional reprogramming via TFEB. Simultaneously, AMPK-TFEB signaling links metabolic stress to lysosomal regeneration, reinforcing immune defense and cellular adaptation. We highlight emerging mechanisms, including ATG8ylation, CASM, Ca2 + leakage, and SG formation, that refine this multilayered response. Mtb virulence factors selectively disrupt these pathways, revealing their relevance to pathogen persistence. Beyond infection, this triadic network maintains lysosomal integrity in neurodegeneration, inflammation, and lysosomal storage disorders. Understanding its modular design reveals novel therapeutic targets and HDTs for combatting drug-resistant TB. This review integrates recent advances into a coherent framework that redefines lysosomal function as a dynamic, immune-regulatory hub essential for cellular resilience under infectious and metabolic stress.

Keywords: Mycobacterium tuberculosis ; ESCRT machinery; LGALSs and TRIM proteins; host-pathogen interaction; lysosomal repair; selective autophagy

DOI: https://doi.org/10.1093/femsre/fuaf040

FEBS J. 2025 Aug 28.

Newly identified properties of known pharmaceuticals and myxobacterial small molecules revealed by screening for autophagy modulators.

Janine Fichtner, Yan Yan Beer, H G Mauricio Ramm, Sabrina Mühlen, Frank Surup, Jennifer Herrmann, Toni Luise Meister, Stephanie Pfaender, Ursula Bilitewski, Mark Brönstrup, Rolf Müller, Manfred Wirth, Eeva-Liisa Eskelinen, Ingo Schmitz.

Autophagy is a cellular degradation and recycling process important for maintaining cellular health and function. It is constitutively active at a low level in eukaryotic cells and can be induced by conditions of cellular stress, such as nutrient starvation. Moreover, autophagy plays an important role in diverse processes such as immunobiology, pathogen infection, ageing, and neurodegenerative and other diseases. Using a high-content fluorescence assay for microtubule-associated protein 1 light chain 3 beta (LC3B), a major player in the autophagic pathway, we screened a library of commercial drugs and natural products for activators and inhibitors of LC3B-positive vesicle accumulation. Positive hits for known autophagy modulators included anisomycin, amphotericin B, carbonyl cyanide m-chlorophenylhydrazone (CCCP) and cytochalasin D. Importantly, we identified several new autophagy modulators, such as aciclovir and myxobacterial vioprolides. Anisomycin, aciclovir and vioprolides promoted intracellular growth of Staphylococcus aureus, a bacterium that is known to be a target of autophagy. In contrast, anisomycin strongly inhibited influenza A virus and SARS-CoV-2 replication. Subsequently, we investigated the influence of these autophagy modulators in a cellular disease model of neuronal vacuolation and spinocerebellar degeneration (NVSD), which is associated with cysteine protease ATG4D mutations. We provide evidence that anisomycin and famciclovir, an aciclovir analogue, can normalise the elevated amount of LC3-positive vesicles in mutant fibroblasts, highlighting their potential for the treatment of NVSD. Thus, the screening method enabled the identification of autophagy-modulating compounds with therapeutic potential.

Keywords: ATG4D; LC3; anti‐infectives; autophagy; drug repurposing; drug screening; natural products

DOI: https://doi.org/10.1111/febs.70243