bims-nocaut 2025-07-13 papers

bims-nocaut

Biomed News

on Non-canonical autophagy

Issue of 2025–07–13
seven papers selected by
Quentin Frenger, University of Strasbourg

The battle between bacterial infection and autophagy in aquatic animals.
ATG16L1 membrane recruitment in autophagy.
Neutrophils display antibacterial defense via non-canonical LC3 decoration of extracellular bacteria.
Autophagic stress activates distinct compensatory secretory pathways in neurons.
Crosstalk Between ALPK1 and STING: A Synergistic Axis in Innate Immune Activation and Human Inflammatory Disease.
Exploiting autophagy and related pathways: pioneering new horizons in cataract therapy.
The cGAS-STING pathway: a dual regulator of immune response in cancer and therapeutic implications.

Front Immunol. 2025 ;16 1614182

The battle between bacterial infection and autophagy in aquatic animals.

Qi Wang, He Xu, Jiaxue Jin, Yankai Yang, Lothar Jänsch, Senlin Li.

  Autophagy is a conserved cellular degradative pathway that has been demonstrated to play a crucial role in the innate immune response to combat infection with a range of pathogenic bacteria via xenophagy. Although this process has been well-described in terrestrial animals, the extent to which autophagy contributes to aquatic animal-bacteria interactions remains poorly understood. Autophagy can directly eliminate intracellular pathogens by acting as a conduit for their lysosomes delivery. Consequently, bacteria have evolved a variety of tactics to evade autophagy. This is accomplished by interfering with autophagy signaling or the autophagy machinery itself. In certain instances, bacteria even utilize autophagy as a means of promoting their growth. This review discusses canonical and non-canonical autophagy pathways and current knowledge of autophagy in aquatic animals. This review illuminates the intricate relationship between autophagy components and intracellular bacteria. It explores how the autophagic machinery senses these bacteria directly or indirectly, the interaction between autophagy and effectors/toxins secreted by bacteria, and how some of these bacterial pathogens evade autophagy.

Keywords:  autophagy; bacteria; immunology; teleost; xenophagy

DOI:  https://doi.org/10.3389/fimmu.2025.1614182
Crit Rev Biochem Mol Biol. 2025 Jul 11. 1-16

ATG16L1 membrane recruitment in autophagy.

Fujing Wei, Nan Qin, Yunling Chen, Zhenzhen Liu, Xiaozhu Zhao, Xiaoying Yu, Ziling Feng, Yu Wang, Aimin Yang, Hongjuan Cui.

  Autophagy, a highly conserved catabolic pathway in eukaryotes, is essential for cellular survival during starvation and for maintaining cellular homeostasis. Central to autophagy is the de novo formation of double-membrane autophagosomes, which requires the orchestrated action of a set of autophagy-related (ATG) proteins. ATG16L1 is a core autophagy protein involved in distinct phases of autophagosome biogenesis, including membrane remodeling and the formation of phagophore-like membrane cups. It interacts with the ATG12-ATG5 conjugate to form the ATG12-ATG5-ATG16L1 complex, which functions as an E3-like enzyme to catalyze LC3 lipidation. The membrane targeting of the ATG12-ATG5-ATG16L1 complex is crucial for regulating autophagy and preventing ectopic membrane engagement. In this review, we summarize and discuss the potential mechanisms underlying ATG16L1 membrane recruitment, focusing on its intrinsic membrane-binding properties and partner-mediated recruitment pathways. We critically explore how these multiple mechanisms collectively ensure the proper localization and function of ATG16L1, thereby regulating the initiation of autophagy, LC3 lipidation, and the sequestration of bacteria during xenophagy.

Keywords:  ATG12–ATG5-ATG16L1 complex; ATG16L1; Autophagy; autophagosome; membrane targeting

DOI:  https://doi.org/10.1080/10409238.2025.2521321
Microbes Infect. 2025 Jul 03. pii: S1286-4579(25)00077-2. [Epub ahead of print] 105545

Neutrophils display antibacterial defense via non-canonical LC3 decoration of extracellular bacteria.

Jurate Skerniskyte, Marina Valente Barroso, Johana Chicher, Philippe Hammann, Valerie Demais, Kathryn Wright, Serge Mostowy, Benoit S Marteyn.

  Neutrophils play a pivotal role in the innate immune response to bacterial infection, being one of the first immune cells to reach infectious sites. Bacterial infection may induce neutrophil degranulation, production of neutrophil extracellular traps (NETs), or pathogen phagocytosis. While LC3 is typically linked to autophagy, here we observed a non-canonical role of LC3 when peripheral neutrophils interact with bacteria both in vivo and in vitro, using Shigella spp. as a model. Upon incubation with neutrophils, extracellular bacteria became labelled by LC3 (LC3+) along with granules-localised antimicrobial components, such as lactotransferrin, defensin, elastase, and myeloperoxidase, as demonstrated by mass spectrometry. Co-localisation of LC3 and plasma membrane-specific dyes indicated that neutrophil plasma membrane-derived elongated structures covering bacteria were responsible for the labelling. This phenomenon was associated with bacterial growth restriction and bacterial cell-death induction. Testing with specific inhibitors demonstrated that this labelling was dependent on functional V-type ATP synthase. Covering bacteria with membrane-derived elongated structures enhanced the subsequent phagocytosis of bacteria by neutrophils. Finally, the LC3 labelling rate increased with higher bacterial burden. In conclusion, we propose that this defense mechanism is beneficial when the burden of bacterial infection overwhelms neutrophils' capacity for phagocytosis.

Keywords:  LC3; Neutrophils; Shigella; autophagy; bacterial infection

DOI:  https://doi.org/10.1016/j.micinf.2025.105545
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2421886122

Autophagic stress activates distinct compensatory secretory pathways in neurons.

Sierra D Palumbos, Jacob Popolow, Juliet Goldsmith, Erika L F Holzbaur.

  Autophagic dysfunction is a hallmark of neurodegenerative disease, leaving neurons vulnerable to the accumulation of damaged organelles and aggregated proteins. However, the late onset of diseases suggests that compensatory quality control mechanisms may be engaged to delay these deleterious effects. Neurons expressing common familial Parkinson's disease-associated mutations in the leucine-rich repeat kinase 2 (LRRK2) exhibit defective autophagy. Here, we demonstrate that both primary murine neurons and human induced Pluripotent Stem Cells (iPSC)-derived neurons harboring pathogenic LRRK2 upregulate the secretion of extracellular vesicles. We used unbiased proteomics to characterize the secretome of LRRK2G2019S neurons and found that autophagic cargos including mitochondrial proteins were enriched. Based on these observations, we hypothesize that autophagosomes are rerouted toward secretion when cell-autonomous degradation is compromised to mediate clearance of undegraded cellular waste. Immunoblotting confirmed the release of autophagic cargos and live-cell imaging demonstrated that secretory autophagy is upregulated in LRRK2G2019S neurons. We also found that LRRK2G2019S neurons upregulate the release of exosomes containing microRNAs. Live-cell imaging confirmed that this upregulation of exosomal release is dependent on hyperactive LRRK2 activity, while pharmacological experiments indicate that this release staves off apoptosis. Finally, we show that markers of both vesicle populations are upregulated in plasma from mice expressing pathogenic LRRK2. In sum, we find that neurons expressing pathogenic LRRK2 upregulate secretory autophagy and the compensatory release of exosomes to mediate waste disposal and transcellular communication, respectively. We propose that this increased secretion contributes to the maintenance of cellular homeostasis, delaying neurodegenerative disease progression over the short term while potentially contributing to neuroinflammation over the longer term.

Keywords:  Parkinson’s disease; autophagy; neurodegeneration; secretion

DOI:  https://doi.org/10.1073/pnas.2421886122
bioRxiv. 2025 Jul 04. pii: 2025.06.30.662363. [Epub ahead of print]

Crosstalk Between ALPK1 and STING: A Synergistic Axis in Innate Immune Activation and Human Inflammatory Disease.

Chong-Shan Shi, Christina Kozycki, Ning-Na Huang, Il-Young Hwang, Dima A Hammoud, Daniel L Kastner, John H Kehrl.

Alpha kinase 1 (ALPK1) is a cytosolic sensor of microbial sugar metabolites that activates NF-κB signaling through phosphorylation of the adaptor protein TIFA. Although canonically linked to NF-κB, individuals with gain-of-function ALPK1 mutations also show features of interferon-driven inflammation. Here, we show that ALPK1 activation enhances multiple outputs of the stimulator of interferon genes (STING) pathway, including both canonical and noncanonical responses such as STING proton channel-dependent LC3B lipidation and NLRP3 inflammasome activation. Furthermore, ALPK1 signaling activates eIF2α, an effector of the integrated stress response. Conversely, STING activation increases ALPK1 protein expression and triggers TIFA-Threonine 9 phosphorylation. Clinically, individuals with ALPK1-mediated disease exhibit premature intracranial mineralization and elevated cerebrospinal fluid neopterin, both associated with dysregulated interferon signaling. These findings support a model of bidirectional signaling between ALPK1 and STING, in which microbial and nucleic acid sensing pathways can amplify one another. This crosstalk provides a mechanistic framework for understanding innate immune signaling relevant to both homeostasis and disease.

DOI: https://doi.org/10.1101/2025.06.30.662363
Apoptosis. 2025 Jul 09.

Exploiting autophagy and related pathways: pioneering new horizons in cataract therapy.

Mehrdad Hashemi, Pezhman Shafiei Asheghabadi, Mahdi Moassesfar, Roya Malek Mohammadi, Nazanin Rafedoust, Maedeh Razeh, Yeganeh Esfahaniolasl, Mahsa Mirzayi, Sahar Keikhavani, Katrin Tajbakhsh, Hajar Heidari, Russel J Reiter, Mina Alimohammadi, Afshin Taheriazam, Najma Farahani, Kiavash Hushmandi, Maliheh Entezari.

  Autophagy is a critical catabolic pathway that facilitates the degradation of intracellular components through lysosomal activity, originally recognized for its role in nutrient recycling during starvation. Recent research has expanded our understanding of autophagy, revealing its involvement in various physiological processes essential for cellular, tissue, and organismal homeostasis. Dysregulation of autophagy has been linked to numerous diseases, including ocular conditions such as cataracts. In human lens fibers, autophagic vesicles containing mitochondria or mitochondrial fragments have been identified, underscoring the importance of autophagy in maintaining lens integrity and transparency. Disruptions in organelle elimination can lead to increased reactive oxygen species (ROS), altering lens homeostasis and contributing to cataract formation. Recent studies have highlighted the complex interplay between autophagy and lens epithelial cells (LECs) in both age-related and diabetic cataract development. In age-related cataracts, increased autophagic activity coincides with elevated apoptosis in LECs, suggesting a bidirectional regulatory role of autophagy in cellular senescence. Additionally, the degradation of SQSTM1/p62 during oxidative stress implicates autophagy in the apoptotic processes associated with senile cataracts. In diabetic cataracts, high glucose levels disrupt the relationship between autophagy and epithelial-mesenchymal transition (EMT) in LECs via the Notch signaling pathway, leading to impaired autophagic function and subsequent cataractogenesis. These findings indicate that autophagy dysregulation is a significant contributor to the pathophysiology of various cataract types. Future research should focus on exploring the therapeutic potential of modulating autophagy to prevent or treat cataracts, investigating specific signaling pathways involved, and identifying biomarkers for early detection. By elucidating the molecular mechanisms underlying autophagy's role in cataract formation, novel targeted therapies may emerge, providing hope for improved management and prevention of this prevalent ocular pathology.

Keywords:  Autophagy; Cataract; Epithelial-mesenchymal transition; Lens epithelial cells; Oxidative stress

DOI:  https://doi.org/10.1007/s10495-025-02134-9
J Transl Med. 2025 Jul 10. 23(1): 766

The cGAS-STING pathway: a dual regulator of immune response in cancer and therapeutic implications.

Zhanghao Huang, Jun Zhu, You Lang Zhou, Jiahai Shi.

  While the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway promotes anti-tumor immunity by detecting cytoplasmic DNA and inducing type I interferons, it also facilitates immune evasion through PD-L1 upregulation. Autophagy enhances cGAS signaling by delivering it to autophagosomes, boosting DNA sensing, while phase separation into liquid droplets further amplifies its activity and regulates autophagy, affecting tumor proliferation. Oxidative stress and DNA damage activate cGAS-STING, triggering pro-inflammatory cytokines that drive chronic inflammation and metabolic disorders. Interactions with immune checkpoint inhibitors augment T cell responses against tumors, yet concurrent PD-L1 induction underscores a complex balance between activation and suppression. Therapeutic strategies-combining DNA damage response inhibitors with checkpoint blockade-show promise in amplifying antitumor immunity. Moreover, post-translational modifications, including m6A methylation and acetylation, fine-tune cGAS function and downstream signaling. Together, these insights reveal the dualistic nature of cGAS-STING in cancer, offering avenues for targeted interventions that leverage its immunostimulatory potential while mitigating mechanisms of immune escape. Additionally, cGAS-driven inflammation links to metabolic dysfunction and chronic disease, underscoring its broad clinical relevance.

Keywords:  Autophagy; Immune response; Therapeutic strategies; Tumor evasion; cGAS-STING pathway

DOI:  https://doi.org/10.1186/s12967-025-06843-2