Aug 2026· Immunity· Vol 59, pp. 2364 - 2382· 0 citations· 263 references
Medicine
TL;DR
It is posited that these are divergent manifestations of a common ancestral homeostatic process of membrane atg8ylation and provide an overview of how they affect immunity and inflammation.
Abstract
Summary Canonical and noncanonical autophagic processes are integrated with innate and adaptive immunity and sterile or pathogen-induced inflammation. In canonical autophagy, double membrane autophagosomes modified by ubiquitin-like ATG8 proteins in a process termed membrane atg8ylation sequester and eliminate intracellular targets such as invading microbes, defunct organelles, aggregates, and inflammatory molecules. Recently, a plethora of noncanonical processes that entail membrane atg8ylation of various intracellular organelles other than autophagosomes have been linked to immunity. This has led to confounding interpretations and conflation of diverse processes as autophagy. Here, we posit that these are divergent manifestations of a common ancestral homeostatic process of membrane atg8ylation and provide an overview of how they affect immunity and inflammation. These relationships are evident in model organisms and are reflected in human genetic predispositions to diseases with immune components. The membrane atg8ylation pathways affect acute and chronic inflammation, infections, autoimmunity, cancer, neurodegeneration, metabolic syndrome, diabetes, and other disorders.
Selective autophagy has emerged as a critical component of plant immunity, yet its role as a dedicated antimicrobial mechanism, xenophagy, remains conceptually underdeveloped. In plants, xenophagy extends beyond bulk degradation to function as a highly regulated, cargo-specific pathway that targets invading pathogens and their effector molecules for autophagic clearance. Recent evidence demonstrates that selective autophagy receptors, particularly NBR1, integrate ubiquitin-mediated recognition with ATG8-dependent sequestration, enabling the elimination of bacterial, fungal, and viral components. However, this process is not merely degradative but operates at the intersection of immune signaling, proteostasis, and cellular decision-making. Here, we synthesize current advances in plant xenophagy and propose a unifying framework in which xenophagy appears to function as a cell-autonomous immune hub comprising three interconnected modules: cargo recognition, selective sequestration, and autophagic execution, dynamically modulated by pathogen-derived countermeasures. We further examine how pathogens subvert or exploit host autophagic machinery, revealing xenophagy as a contested interface in plant-pathogen interactions. By integrating molecular, cellular, and cross-kingdom perspectives, we highlight key conceptual gaps, including the specificity of cargo selection, the regulatory logic of receptor engagement, and the coordination between autophagy and canonical immune pathways. Resolving these gaps will be essential for repositioning xenophagy as a central determinant of plant immune competence, with significant implications for engineering disease-resistant crops.
Laha Supriya, Deepika Dake, Pooja Shukla et al.· Plant, Cell and Environment· 0 citations
Abstract Autophagy is a highly conserved cellular degradative pathway in eukaryotes that exerts a dual regulatory role in the host antiviral defense. On the one hand, as an essential component of the host antiviral defense network, autophagy participates in the direct degradation of viral components, synergistically modulates innate immune signaling pathways including TLRs, RLRs, and cGAS-STING, and regulates adaptive immune responses such as MHC class I/II-mediated antigen presentation. On the other hand, diverse viruses have evolved sophisticated immune evasion mechanisms during long-term coevolution with the host. These viruses target key steps of autophagy, including initiation, membrane nucleation, elongation, maturation, and lysosomal fusion, to hijack or suppress the autophagic pathway and facilitate their replication. The regulation of autophagy by different viruses exhibits remarkable molecular specificity. In-depth dissection of these molecular mechanisms underlying autophagy-virus interactions will provide novel insights into the pathogenesis of viral diseases. This review systematically summarizes the core process of autophagy and its multiple regulatory mechanisms in antiviral immunity. We further highlight how viruses employ specific molecular strategies to target distinct stages of autophagy during infection, thereby hijacking the autophagic pathway to complete their replication cycles and pathogenic progression.
Autophagy is an evolutionarily conserved lysosomal recycling system that integrates nutrient sensing, organelle quality control, proteostasis, cellular stress responses and metabolic adaptation. Autophagy is particularly relevant for post-mitotic tissue such as neurons, skin, and immune cells. Monogenic disorders disrupting autophagy or closely coupled endolysosomal trafficking pathways have recently emerged as a recognizable group of inherited metabolic diseases. These conditions are individually rare inborn errors of metabolism and collectively important because they bridge neurodevelopmental, neuromuscular and neurodegenerative disorders, including hereditary forms of Parkinson's disease, spastic paraplegias and neurodegeneration with brain iron accumulation. Multisystem involvement is common but variable. The prototypic disorder is EPG5-related Vici syndrome, in which defective autophagosome-lysosome fusion causes severe neurodevelopmental and multisystem disease. Other disorders may affect any step of the pathway, from phosphatidylinositol 3-phosphate effector biology and ATG conjugation/lipidation to autophagosome maturation, ATG9 trafficking, HOPS/CORVET-related vesicle trafficking (including VPS16 and VPS33A), autophagosome-lysosome fusion, autolysosome reformation and lysosome-mTOR signaling. Clinically, affected individuals commonly present with global developmental delay and/or intellectual disability, epilepsy, movement disorders including dystonia, parkinsonism, ataxia and spasticity, and both neuropathic and myopathic neuromuscular manifestations. A biphasic course with progressive neurodegeneration and variable multisystem (including ocular, cardiac, immunological, cutaneous and growth) involvement are important clinical clues. Diagnosis relies on careful phenotyping, brain MRI, targeted metabolic exclusion of mimics, genomic sequencing and functional assays in patient-derived cells as required. Supportive multidisciplinary management is essential. No disease-modifying therapy is currently established in humans, but pathway-based cellular assays, model systems and small-molecule or gene-replacement strategies are creating a rational therapeutic pipeline. Importantly, IEMbase dyadic nomenclature with system-level clinical annotations provides a standardized framework for quantifying shared phenotypic signatures across these ultra-rare conditions. This review summarizes pathobiochemistry, genetics, clinical presentation, diagnosis and treatment prospects for inherited disorders of autophagy.
H. Jungbluth, H. Dafsari, Carlos R. Ferreira et al.· Molecular Genetics and Metab...· 0 citations
Autophagy, as a core mechanism for maintaining cellular homeostasis, influences differentiation and functional activation of immune cells by regulating metabolic reprogramming. Crucially, autophagy serves as a molecular switch that precisely modulates differentiation and subsequent cell fate decisions. It achieves this by eliminating intracellular danger signals or key complexes, thereby determining whether immune cells undergo PANoptosis, an inflammatory death mode that integrates features of pyroptosis, apoptosis and necroptosis. The present review systematically discusses the regulatory role of autophagy in the developmental, differentiation and metabolic pathways of various immune cells. Furthermore, it elucidates the mechanistic details by which autophagy, and particularly mitophagy, dampens excessive PANoptosis activation through the elimination of danger signals (such as mitochondrial DNA and reactive oxygen species) or the degradation of PANoptosome components. Additionally, it clarifies the molecular mechanism by which autophagy dysregulation, induced by specific pathological conditions, leads to inflammatory responses and immunopathological damage. Overall, this review establishes the significance of the autophagy-PANoptosis axis in the development and progression of autoimmune diseases and tumors, providing a solid theoretical foundation for the optimization and innovation of therapeutic strategies for these diseases.
Ya-Nan Guo, Xin-Yue Zhou, Yi-Xiao Tian et al.· International Journal of Mol...· 0 citations
Autophagy is a highly conserved degradative and recycling pathway essential for maintaining cellular homeostasis. Although its molecular machinery is well characterized in yeast and mammalian systems, it is less studied in the early‐diverging apicomplexan parasite Plasmodium, the causative agent of malaria. Plasmodium possesses a reduced yet functional repertoire of autophagy‐related (ATG) proteins, suggesting adaptations of this pathway to parasite‐specific biology. Among these, ATG8, a ubiquitin‐like protein, has emerged as a central marker and key effector of plasmodial autophagy. Its branched localization and association with the relict plastid (apicoplast) membrane indicate roles beyond canonical degradative autophagy, particularly in organelle maintenance and biogenesis. ATG7, an essential E1‐like enzyme, activates ATG8 and facilitates its lipidation, thereby regulating organelle turnover and development. This process is further supported by a conserved conjugation system involving ATG3 (E2‐like enzyme) and the ATG12, ATG5, ATG16 complex, functioning as a ligase to enable ATG8 membrane association. ATG4, a cysteine protease, is critical for recycling lipidated ATG8 and maintaining its cytosolic pool, while the homolog Otu can partially compensate for its function. ATG18 also plays an important role in apicoplast biogenesis and maintenance. Collectively, these findings highlight both canonical and non‐canonical roles of autophagy proteins in Plasmodium, driving metabolic reprogramming, intracellular remodeling, and stage‐specific differentiation, and support their potential as targets for new antimalarial therapies.
Macroautophagy/autophagy is a well-established homeostatic mechanism that contributes to the integrity of multiple regulatory biological activities including but not limited to the gastro-intestinal tract and cognitive integrity. Autophagy also plays a central role in tissue regeneration, metamorphosis and development whereas defects in autophagy are associated with a wide range of disorders including metabolic diseases such as diabetes, organ pathophysiologies including liver, lung and heart disease, cancer, and microbial infection. In the field of cancer therapy, most research efforts have focused on cytoprotective autophagy, with substantial preclinical and clinical studies designed to interrogate the outcomes of pharmacologically (or genetically in preclinical work) inhibiting autophagy to enhance the efficacy of chemotherapeutic agents. There is lesser but nevertheless robust evidence for the cytotoxic function of autophagy while our laboratory and a few others have identified the nonprotective form of this cellular response. However, cytostatic autophagy, a distinct functional outcome of autophagy characterized by sustained proliferative arrest, has remained relatively underexplored. Cytostatic autophagy can be defined as a cellular condition in which autophagy activation coincides with durable proliferative arrest, and in which genetic or pharmacological inhibition of autophagy relieves the growth-arrest phenotype without inducing overt cytotoxicity. In this review, we provide the first comprehensive synthesis of the scientific literature addressing cytostatic autophagy, tracing its historical development and consolidating the experimental evidence that led to its current conceptual definition. We further discuss the molecular mechanisms underlying cytostatic autophagy, including the selective degradation of key cell-cycle regulators and the interplay between autophagy and senescence-associated signaling pathways.
Ahmed M. Elshazly, Aya A Elzahed, Shady Allam et al.· Autophagy· 0 citations
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