Findings indicate that H₂O₂ has multifaceted effects on AaAtg4 in a dosage-dependent or threshold-specific manner, which may position AaAtg4 as a central integrator of cellular stress responses and secondary metabolism, thereby advancing the understanding of fungal pathogenicity and environmental adaptation.
Abstract
Introduction Autophagy-related protease AaAtg4 was previously identified as a key regulator in the pathogenic fungus Alternaria alternata, orchestrating a complex interplay among autophagy, oxidative stress resistance, iron homeostasis, and ACT toxin biosynthesis. The underlying mechanisms of AaAtg4 in relation to oxidative stress response remain unknown. Methods Genetic and biochemical analyses. Results In this study, we examined the effect of hydrogen peroxide (H₂O₂) on AaAtg4. Functioning as a cysteine protease, AaAtg4 directly interacts with the AaAtg8 ubiquitin-like protein and is indispensable for AaAtg8 processing and autophagosome formation, with its enzymatic activity modulated by oxidative cues. H₂O₂ differentially impacts AaAtg4 activity, phosphorylation, binding with AaAtg8, AaAtg8 lipidation/delipidation, and autophagy. H₂O₂ has biphasic effects on AaAtg4. Moderate H₂O₂ levels enhance AaAtg4 activity and autophagy, whereas excessive H₂O₂ suppresses both, revealing a threshold-dependent redox regulation. Furthermore, AaAtg4 interacts with the stress-responsive mitogen-activated protein kinase AaHog1, which modulates its phosphorylation under conditions less conducive to autophagy and thus, reinforces a dynamic signaling axis. Discussion These findings indicate that H₂O₂ has multifaceted effects on AaAtg4 in a dosage-dependent or threshold-specific manner. These regulatory mechanisms may position AaAtg4 as a central integrator of cellular stress responses and secondary metabolism, thereby advancing our understanding of fungal pathogenicity and environmental adaptation.
It is demonstrated that AaAtg4 is important for spore germination, siderophore biosynthesis, iron acquisition, oxidative stress resistance, and toxin production, thereby establishing its critical role in A. alternata virulence.
Hsin-Yu Lu, C. H. Y. Choo, Je-Jia Wu et al.· Fungal Genetics and Biology· 0 citations
Upon exposure to stress, cells activate a variety of stress-response and quality-control mechanisms to maintain homeostasis. Dysregulation of these processes is implicated in numerous diseases, including cancer, liver disorders, and neurodegenerative diseases. p62/Sequestosome 1 (SQSTM1) is a multifunctional protein that plays a central role in protein homeostasis and stress responses by regulating autophagy and signal transduction pathways. Through its multiple protein-interacting domains, p62 functions both as a scaffold for selective autophagic degradation and as a signaling hub. Since our previous review of p62 a decade ago, substantial progress has been made in elucidating its molecular functions and physiological roles. Notably, p62 undergoes liquid-liquid phase separation with ubiquitinated proteins to form membraneless condensates, termed p62 bodies, when cells are exposed to proteotoxic stress. By sequestering specific proteins, p62 bodies act as platforms for autophagy-dependent degradation and stress signaling. These findings have substantially revised our view of p62 function, which was previously considered primarily as a receptor simply linking ubiquitinated substrates to autophagic membranes and connecting signaling molecules. This conceptual shift from one-to-one molecular interactions to multivalent, multimolecular, higher-order assemblies has fundamentally redefined the functional landscape of p62. In this review, we highlight how p62 bodies integrate selective autophagy and stress signaling, with a particular emphasis on their emerging roles in disease pathogenesis and their potential as therapeutic targets.
Jun-ichi Sakamaki, Masaaki Komatsu· The FEBS Journal· 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.
Pathogen-induced reactive oxygen species (ROS) act as key signaling molecules in plant immunity, but their integration with epigenetic regulation remains unclear. Here, we identify the rice (Oryza sativa) histone deacetylase OsHDA705 as a redox sensor that coordinates immunity through oxidative post-translational modifications (PTMs). Pathogen-induced ROS oxidizes OsHDA705 at cysteine 256 (C256), blocking its deacylase activity. This oxidation promotes hyperacylation of the transcription factor OsIPA1 and histones, thereby activating defense gene expression. We further show that the catalase OsCATB functions as a redox mediator, reducing oxidized OsHDA705 to restore its deacetylase activity, thereby re-establishing the suppression of immunity. The fungal pathogen Ustilaginoidea virens hijacks this process via the secreted effector UvSE1, which physically interacts with the host catalase OsCATB to boost its ROS-scavenging activity, thereby reducing the oxidation level of OsHDA705. Genetic disruption of the OsCATB-OsHDA705 module enhances broad-spectrum disease resistance. Our findings reveal a pathogen strategy to reprogram the host's redox-epigenetic regulation and establish reversible histone deacetylase oxidation as a molecular switch regulating immune transcription in plants.
Yuan Fang, Rui Wang, Yuhang Duan et al.· The Plant Cell· 0 citations
Fungi have evolved sophisticated mechanisms to survive in complex environments. Nematode-trapping fungi (NTF) sense and recognize nematode prey to transition from a saprophytic to predatory lifestyle, rendering them promising biocontrol agents against plant-parasitic nematodes. Ubiquitination is essential for eukaryotic cellular homeostasis, yet its regulation of NTF development and pathogenicity remains unclear. Here, we identify the conserved E3 ubiquitin ligase AoRsp5 as a critical factor for all major life stages of Arthrobotrys oligospora. Knockout of rsp5 impairs Endosomal Sorting Complex Required for Transport (ESCRT)-mediated endocytosis and compromises plasma membrane integrity. These defects trigger disturbed cellular iron homeostasis and ferroptosis-like cell death, accompanied by global dysregulation of protein phosphorylation and ubiquitination as well as prominent suppression of MAPK cascades, which further attenuate virulence-associated signaling. Overall, our findings reveal a pivotal role for Rsp5-mediated ubiquitination in coordinating cellular homeostasis and developmental transitions in NTF.
Xiqi Zhang, Hai-Long Pu, Run-Liu He et al.· Journal of Fungi· 0 citations
Sugar starvation during seed germination requires coordinated regulation of reserve mobilization, redox homeostasis, and intracellular recycling. In lupin seeds, asparagine is a major nitrogen-rich metabolite, but its role in starvation-induced autophagy and redox regulation remains unclear. Here, isolated embryonic axes of white lupin (Lupinus albus L.) and Andean lupin (Lupinus mutabilis Sweet) were cultured in vitro under sucrose-fed or sugar-starved conditions, with or without asparagine supplementation. Using transcriptomic, proteomic, immunoblot, enzymatic, antioxidant activity, and confocal microscopy analyses, we show that sugar starvation induced redox- and autophagy-related reprogramming, including changes in reactive oxygen species (ROS)-related proteins, catalase accumulation, autophagy-related (ATG) gene expression, vacuolar hydrolase-related responses, and proteolytic activity. Peroxisome-associated components, including glycolate oxidase, acyl-CoA oxidase, and catalase, were strongly affected, indicating dynamic remodeling of peroxisome-related metabolism during starvation. Asparagine modified this response by increasing antioxidant capacity and catalase accumulation under sugar starvation, while reducing detectable autophagosome number, many ATG and vacuolar hydrolase transcripts, and proteolytic activity. Together with previous evidence for asparagine-induced accumulation of autophagic bodies in vacuoles, these results are consistent with asparagine-dependent modulation of several autophagy-related processes rather than with an effect restricted to a single autophagic step. White and Andean lupin shared the same general regulatory framework but differed in response intensity. Thus, asparagine links nitrogen status with redox stabilization, vacuolar catabolism, and autophagy-related dynamics in sugar-starved lupin embryonic axes.
Szymon Stefaniak, Karolina Wleklik, K. Nuc et al.· International Journal of Mol...· 0 citations
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