bims-nocaut 2026-02-01 papers

Issue of 2026–02–01
five papers selected by
Quentin Frenger, University of Strasbourg

Pathogens. 2026 Jan 09. pii: 70. [Epub ahead of print]15(1):

Hepatocyte Autophagy in Malaria: Current Concepts, Emerging Mechanisms, and Future Therapeutic Directions.

Afiat Berbudi, Shafia Khairani, Endang Yuni Setyowati, Alexander Kwarteng.

The liver stage of Plasmodium infection represents a critical bottleneck in malaria pathogenesis and a unique interface between parasite development and hepatocyte-intrinsic immunity. Recent evidence suggests that hepatocytes do not eliminate liver-stage parasites through canonical xenophagy, as previously assumed, but instead employ a noncanonical autophagy response known as the conjugation of ATG8 to single membranes (CASM). CASM drives rapid lipidation of LC3 onto the parasitophorous vacuole membrane (PVM) via a V-ATPase-ATG16L1-dependent mechanism, thereby activating the Plasmodium-associated autophagy-related (PAAR) response. This process represents a major hepatocyte-intrinsic mechanism that limits early liver-stage parasite development. Plasmodium liver-stage parasites have evolved specialized strategies to counteract this host defense. The PVM proteins UIS3 and UIS4 enable parasite evasion by sequestering LC3 and remodeling perivacuolar actin, thereby preventing endolysosomal fusion and inhibiting PAAR execution. In parallel, parasites selectively exploit host autophagy components-particularly GABARAP paralogs-to activate TFEB, promoting lysosomal biogenesis and improving access to host-derived nutrients. These interactions highlight autophagy as both a protective and parasite-supportive pathway, depending on the molecular context. Understanding how CASM, PAAR, and parasite evasion mechanisms intersect is crucial for designing pathway-selective interventions that amplify hepatocyte-intrinsic clearance while avoiding the inadvertent enhancement of parasite-supportive autophagy programs. Selective modulation of noncanonical autophagy offers a promising avenue for host-directed therapies that restrict liver-stage development while limiting the emergence of antimalarial resistance. This review synthesizes recent advances in the mechanistic interplay between Plasmodium liver stages and hepatocyte autophagy, identifies major knowledge gaps, and outlines future directions for translating these discoveries into therapeutic innovation.

Keywords: Plasmodium; autophagy; endosomes; host–pathogen interactions; liver; malaria

DOI: https://doi.org/10.3390/pathogens15010070

Front Immunol. 2025 ;16 1650789

Endocytosis and non-canonical autophagy mediate extracellular histones cytotoxicity in vascular models of sepsis.

C Garcés, P Tascón, Luis Diago-Domingo, A J Ibáñez, G Herrera, L R Rodríguez, K Salewskij, G Jonsson, J M Penninger, C Romá-Mateo, F V Pallardó.

Introduction: Sepsis, a widespread global ailment, involves an exaggerated immune response, leading to hyperinflammation and immunosuppression. Extracellular histones, released during hyperinflammation as part of the defensive response against pathogens, significantly contribute to sepsis pathogenesis, compromising viability of the host's endothelial cells and contributing to organ failure.
Methods: This study explores the link between cytotoxic effects of extracellular histones and endocytosis mechanisms in human umbilical vein endothelial cells (HUVECs) and blood vessel organoids (BVOs) incubated with extracellular histones and different modulators of endocytosis mechanisms.
Results: Exposure to various doses of purified extracellular histones in both HUVECs cultures and BVOs revealed sub-lethal doses leading to histone entry and colocalization with the autophagy mediator LC3B, whereas high doses induced cytotoxicity. Incubating cells or organoids at low temperature before histone exposure prevented entry, reducing colocalization with LC3B and cell death; moreover, inhibition of clathrin-mediated endocytosis abrogated histone entry into HUVECs and prevented their cytotoxic effects, whereas inhibition of caveolin-mediated mechanisms had no effect.
Discussion: In summary, this study offers insights into histones' cytotoxicity and functional interactions with the LC3B-mediated, non-canonical autophagy pathway, enhancing our understanding of the molecular bases of sepsis pathophysiology within HUVEC and blood vessel organoids.

Keywords: HUVEC; LC3-associated endocytosis; LC3B; blood vessel organoids; endocytosis; extracellular histones; non-canonical autophagy; sepsis

DOI: https://doi.org/10.3389/fimmu.2025.1650789

Cells. 2026 Jan 06. pii: 102. [Epub ahead of print]15(2):

From Hero to Hijacker: Autophagy's Double Life in Immune Patrols and Cancer Escape.

Flavie Garampon, Aurore Claude-Taupin.

Cells are constantly exposed to mechanical forces that shape their behavior, survival, and fate. The autophagy machinery emerges as a central adaptive pathway in these processes, acting not only as a metabolic and quality control mechanism but also as a key regulator of membrane dynamics and mechanotransduction. Here, we review how mechanical stress influences autophagy initiation, autophagosome maturation, and lysosomal function across different cell types. We discuss parallels between leukocyte diapedesis and circulating tumor cell (CTC) extravasation, two processes that involve profound mechanical challenges and rely on autophagy-related pathways to maintain cell integrity and enable transendothelial migration. Special attention is given to the dual role of autophagy-related proteins (ATGs) in these contexts, ranging from cytoplasmic degradation dependent on lysosomal fusion to secretory functions. Understanding how mechanical forces modulate autophagy and ATG-dependent pathways may reveal novel insights into immune regulation, tumor dissemination, and potential therapeutic targets aimed at controlling inflammation and metastasis.

Keywords: autophagy; cancer; diapedesis; extravasation; immunology; mechanobiology; migration; shear stress

DOI: https://doi.org/10.3390/cells15020102

Autophagy. 2026 Jan 28. 1-15

Deubiquitinase USP15 restricts LC3-dependent targeting of Mycobacterium tuberculosis.

Kathryn C Rahlwes, Priscila C Campos, Beatriz R S Dias, Paola K Párraga Solórzano, Michael U Shiloh.

Macroautophagy/autophagy enables macrophages to degrade intracellular Mycobacterium tuberculosis (Mtb), and this defense depends on E3 ubiquitin ligases such as PRKN/PARKIN/PARK2 and SMURF1, which tag Mtb-associated structures for lysosomal clearance. Deubiquitinases (DUBs) counter ubiquitin ligases by removing ubiquitin from molecular targets. We hypothesized that DUBs might offset ubiquitin ligase activity and negatively regulate host immunity to Mtb. Here, we identify USP15 (ubiquitin specific peptidase 15) as a negative regulator of MAP1LC3/LC3-dependent targeting pathways (consistent with xenophagy or CASM/LAP-related ATG8ylation) that mediate macrophage immunity to Mtb. Using a targeted knockdown screen in mouse macrophages, we found that Usp15 loss increased K63-linked ubiquitination and LC3 recruitment to Mtb-associated structures, leading to reduced bacterial replication. These effects required USP15's catalytic activity and were reversed by knockdown of PRKN or inhibition of autophagy initiation. In primary human macrophages, USP15 knockdown similarly enhanced LC3 targeting and restricted Mtb growth. Importantly, pharmacological inhibition of USP15 with a selective small molecule decreased Mtb burden in human macrophages. Our findings identify USP15 as a suppressor of macrophage immunity and suggest that targeting deubiquitinases may represent a promising host-directed therapeutic strategy against tuberculosis.Abbreviations: CFU: colony-forming unit; DUBs: deubiquitinases; K48-Ub: K48-linked ubiquitin; K63-Ub: K63-linked ubiquitin; Mtb-pLux: luminescent Mtb strain Mtb; Mycobacterium tuberculosis; MOI: multiplicity of infection; NTC: non-targeting control; TB: tuberculosis.

Keywords: Deubiquitinase; host-directed therapy; innate immunity; tuberculosis; ubiquitin; xenophagy

DOI: https://doi.org/10.1080/15548627.2026.2618632

Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00031-6. [Epub ahead of print]

Lysosomes as hubs of metabolic sensing and cellular homeostasis.

Aakriti Jain, Roberto Zoncu.

Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular degradation, including amino acids, lipids, and iron, are exported by dedicated transporters for utilization in the cytoplasm. Nutrient transport across the lysosomal membrane is coupled to its sensing by specialized signaling complexes on the cytoplasmic face, which, in response, mediate communication with other organelles and control cell-wide programs for growth, catabolism, and stress response. Lysosomes acquire specialized sensing-signaling features in immune cells, where they shape antigen processing, innate immune signaling, and inflammatory cell death, and in neurons, where they act as sentinels of proteostatic and mitochondrial stress, supporting local translation, organelle quality control, and neuroimmune crosstalk. We highlight recently identified pathways and players that position lysosomes as integrators of nutrient status and organelle health to drive tissue-specific physiology.

Keywords: amyloid; autophagy; inflammation; lysosome; mTORC1; metabolites; neurodegeneration; organelle contacts; signaling

DOI: https://doi.org/10.1016/j.molcel.2026.01.011