Autophagy最新文献

Accumulation of lipid droplets (LDs) in cardiomyocytes contributes to developmentof septic cardiomyopathy, a fatal complication of critical illness in patients.Lipophagy is a selective autophagic mechanism for LD degradation. This processis inhibited by MTOR, but is activated by PNPLA2 via its binding with LC3-II toform LD-containing autophagosomes. However, optimum lipophagic interventions tomanage septic cardiomyopathy have not been developed, thus furtherinvestigation is required to identify novel regulators of lipophagy in theseptic heart. HSPA12A (heat shockprotein 12A) encodes an atypical member of the HSPA/HSP70family. Here, we report that sepsis decreased HSPA12Aexpression in cardiomyocytes, whereas cardiomyocyte-specific HSPA12Aoverexpression aggravated sepsis-induced cardiomyocyte death and cardiacdysfunction in mice. Notably, HSPA12A promoted sepsis-induced LD accumulationin cardiomyocytes. By contrast, HSPA12A inhibited lipophagy in septiccardiomyocytes, as reflected by a decreased level of LD-containing autophagosomes,a reduced content of LC3-II, and an increased level of SQSTM1/p62. In-depthmolecular analysis revealed that HSPA12A increased phosphorylation of MTOR andthus its binding to PNPLA2 on LDs. MTOR thereby competed against LC3-II inbinding with PNPLA2 to suppress LD-containing autophagosome formation subsequentlyimpairing lipophagy and ultimately promoting cardiomyocyte death to exaggerate septiccardiomyopathy. We demonstrated that MTOR competed against LC3-II in bindingwith PNPLA2 to inhibit lipophagy and also identified HSPA12A as a driver ofthis competition with MTOR to impair lipophagy for exaggerating septic cardiomyopathy. Strategiesthat inhibit HSPA12A in cardiomyocytes might be a potential therapeuticintervention for septic cardiomyopathy.

Macroautophagy/autophagy has long been viewed as being strictly dependent on vacuolar or lysosomal acidity, with the vacuolar-type H⁺ -translocating ATPase (V-ATPase) functioning mainly as a proton pump that sustains degradation. Our recent paper overturns this paradigm, revealing that loss of V-ATPase activity paradoxically induces a selective autophagy program in nutrient-replete Saccharomyces cerevisiae. Vacuolar deacidification triggers a signaling cascade through the Gcn2-Gcn4/ATF4 integrated stress response, which drives Atg11-dependent ribophagy even when TORC1 remains active. This "V-ATPase-dependent autophagy" operates as a self-corrective feedback loop: when the vacuole's degradative capacity falters, it signals its own dysfunction to restore homeostasis. Tryptophan and NAD⁺ metabolism modulate this response, linking metabolic balance to autophagy induction. This discovery reframes the vacuole/lysosome from a passive endpoint to an active sensor of cellular integrity. It also challenges the use of V-ATPase inhibitors such as bafilomycin A₁ as neutral autophagy flux blockers, because inhibition itself can stimulate autophagy induction. Collectively, these findings position the V-ATPase as a bidirectional regulator - both gatekeeper and sentinel - governing how cells translate organelle stress into adaptive autophagy.

Chaperone-mediated autophagy (CMA), once considered a secondary or auxiliary degradation pathway, is now recognized as a central regulator of synaptic proteostasis. A recent study by Khawaja et al. (2025) in Nature Cell Biology provides compelling evidence that CMA actively remodels the synaptic proteome in a sex-specific manner. Using a conditional knockout strategy based on Lamp2a-floxed mice crossed with a Camk2a-Cre driver line to achieve excitatory neuron-specific deletion of Lamp2a in adult mice, the authors revealed sexually divergent synaptic phenotypes: females exhibit enhanced presynaptic neurotransmitter release and GRIN/NMDAR-mediated plasticity, while males show increased postsynaptic GRIA/AMPAR activity due to impaired receptor endocytosis. These changes are driven by sex-specific degradation of synaptic proteins such as SYN1 (synapsin I) in females and AP2A/α-Adaptin in males. Importantly, reactivation of CMA - either genetically or pharmacologically - rescues synaptic dysfunction, seizure susceptibility, and memory deficits in aged mice and Alzheimer disease models. This commentary contextualizes these findings within the broader framework of activity-dependent proteostasis, sex-specific autophagy modulation, and therapeutic potential of CMA in brain aging and neurodegeneration.

Senecavirus A (SVA) belongs to the picornaviruses and has emerged as a promising candidate for oncolytic virotherapy in humans. Understanding the immune suppression mechanisms employed by SVA can help optimize its therapeutic efficacy as an oncolytic virus while simultaneously minimizing its immune suppressive effects on normal tissues. In this study, we identified a novel function of the SVA structural protein VP2 as a key viral immune suppressive factor during SVA infection. VP2 targets and degrades IKBKE/IKKε, a key component of the innate immune pathway, thereby suppressing host innate immune responses. It preferentially interacts with the selective autophagic receptor CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2), which then recognizes the K33-linked ubiquitinated IKBKE and delivers it to phagophores for degradation. The E3 ligase RNF114 is responsible for catalyzing the K33-linked ubiquitination of IKBKE at Lys490, and VP2 significantly promoted this modification, which further accelerated IKBKE degradation. Importantly, we found that picornavirus VP2 proteins share this conserved mechanism in degradation of IKBKE and suppression of host innate immunity. These data elucidate the negative regulatory mechanism involving the VP2-RNF114-IKBKE/IKKε-CALCOCO2 axis, and reveal an immune evasion strategy employed by picornaviruses. These findings will provide valuable insights for the development of picornaviral vaccines and antiviral/antitumor therapeutics.Abbreviations: 3-MA: 3-methyladenine; ATG5: autophagy related 5; ATG7: autophagy related 7; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; co-IP: co-immunoprecipitation; DAPI: 4',6-diamidino-2'-phenylindole; EV71: enterovirus 71; FMDV: foot-and-mouth disease virus; hpi: hours post-infection; IFN: interferon; IKBKE/IKKε: inhibitor of nuclear factor kappa B kinase subunit epsilon); ISGs: IFN-stimulated genes; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MG132: cbz-leu-leu-leucinal; MOI: multiplicity of infection; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; RNF114: ring finger protein 114; RT-PCR: real-time polymerase chain reaction; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; SVA: Senecavirus A; TCID₅₀: 50% tissue culture infectious doses. TOLLIP: toll interacting protein; TRIM17: tripartite motif containing 17; TRIM25: tripartite motif containing 25; TRIM28: tripartite motif containing 28; TRIP12/THRI12: thyroid hormone receptor interactor 12; Ub: ubiquitin; Vec: vector; WCL: whole-cell lysate; WT: wild-type.

Transfer RNA-derived small RNAs (tDRs) have transcended their traditional roles in protein synthesis and have emerged as crucial regulators of cellular homeostasis. Li et al. (2025) underscored this by identifying tRNA-Asp-GTC-3'tDR as a tDR responsive to hypoxic conditions, which confers renal protection through a distinctive macroautophagy/autophagy mechanism. This tDR adopts a G-quadruplex structure that sequesters PUS7 (pseudouridine synthase 7), thereby disrupting the pseudouridylation of histone mRNAs and directing them toward degradation via autophagosome-lysosome pathways, a mechanism termed "RNautophagy." Clinically, elevated levels of tRNA-Asp-GTC-3'tDR in conditions such as preeclampsia and early chronic kidney disease suggest a conserved evolutionary pathway for renal protection in humans. Experimental studies in mice have demonstrated that therapeutic enhancement of tDR mitigates renal inflammation, fibrosis, and damage, whereas its inhibition exacerbates these conditions. This establishes a novel paradigm linking RNA biology and autophagy regulation, paving the way for innovative precision RNA-based therapies for kidney diseases.Abbreviations: mRNAs: messenger RNA; PUS7: pseudouridine synthase 7; tDRs: transfer RNA-derived small RNAs; tRNA-Asp-GTC-3'tDR: transferRNA-aspartic acid-GTC-codon-3'terminal deoxyribonucleotide.

Macroautophagy/autophagy was previously shown to play a critical role in the hippocampus for memory formation, with age-related autophagy deficits being further linked to cognitive decline. However, the neuronal subtypes where autophagy is required to form new memories remain unknown. Given the well-established role of PVALB (parvalbumin) interneurons in hippocampus-dependent memory formation and consolidation, we examined whether autophagy in these cells is required for such complex behaviors. We show that contrary to other neuronal subtypes, the vast majority of PVALB neurons, with the exception of cerebellar Purkinje cells, survive and are maintained long-term independently of autophagy. However, autophagy controls the homeostasis of mitochondria, endoplasmic reticulum, and synaptic proteins within PVALB interneurons, ultimately regulating their synaptic excitation, neuronal excitability and excitation-inhibition balance in the hippocampus. Consequently, mice with conditional impairment of autophagy in PVALB-expressing neurons exhibit impaired inhibitory neurotransmission and deficits in hippocampus-dependent memory. Taken together, these findings identify PVALB interneurons as key cellular substrates of autophagy in the context of learning and memory.Abbreviation: ATG5: autophagy related 5; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CA1: cornu ammonis 1; CALCOCO1: calcium binding and coiled coil domain 1; ER: endoplasmic reticulum; GABA: gamma-aminobutyric acid; GRIA/AMPAR: glutamate receptor, ionotropic, AMPA; GRIN2A/NR2A/GluN2A: glutamate receptor, ionotropic, NMDA2A (epsilon 1); PRKN: parkin RBR E3 ubiquitin protein ligase; PC: pyramidal cells; PJ: Purkinje; PVALB: parvalbumin; RTN3: reticulon 3; SQSTM1/p62: sequestosome 1.

Radiotherapy is a fundamental step in the combined treatment of glioblastoma (GBM), while radioresistance of GBM causes limitation of therapeutic efficacy. Natural killer (NK) cells, a potential target of immunotherapy, have attracted considerable attention due to the robust cancer cell-targeted cytotoxicity in combined treatment with radiotherapy, suggesting NK cell regulation might be a radiosensitization strategy. Here we show that a cytotoxic subset of NK cells could be stimulated by ionizing radiation (IR) and accumulate in the GBM tumor microenvironment (TME). Co-culturing with NK cells significantly enhances the GBM cell response to IR, and pharmaceutically depleting NK cells in mice elevates IR-induced tumor growth delay. Specifically, GZMB should be the radiosensitization effector secreted by NK cells. Suppressing GZMB activity remarkably impairs NK-mediated GBM radiosensitization. Meanwhile, administrating exogenous GZMB improves irradiation dose-survival response in vitro or in a xenograft model. Mechanically, GZMB blocks autophagosome-lysosome fusion in GBM cells by directly recognizing and cleaving SDC1, a key regulator of autophagosome maturation, at the valine 225 and aspartate 228 sites. Uncleavable mutation of SDC1 reverses GZMB-mediated radiosensitization in GBM. Further studies demonstrate that cleavage of SDC1 obstructs the localization of TGM2, a key MAP1LC3/LC3 recognizer, on the lysosome surface. Clinical data reveal GBM patients with an SDC1 valine 225 or aspartate 228 mutation display lower response to radiotherapy. In this study, we disclose the critical role of NK cells in tumor radiotherapy through secreting GZMB and impeding autophagosome maturation, as well as propose a potential strategy combining radiotherapy and NK-based immunotherapy against radioresistant GBM.Abbreviations: DEGs: differentially expressed genes; GBM: glioblastoma; GZMB: granzyme B; IL: interleukin; IR: ionizing radiation; IRS: immunoreactive score; LAMP: lysosomal associated membrane protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; mSDC1: mutant SDC1; NK: natural killer; PRF1: perforin 1; SDC1: syndecan 1; SNAP29: synaptosome associated protein 29; SQSTM1: sequestosome 1; STX17: syntaxin 17; TGM2: transglutaminase 2; TME: tumor microenvironment; TGD: tumor growth delay; VAMP8: vesicle associated membrane protein 8; WT: wild type.

Macroautophagy/autophagy exerts multilayered protective functions in intestinal epithelial cells (IECs) while a loss-of-function genetic variant in ATG16L1 (autophagy related 16 like 1) is associated with risk for developing Crohn disease (CD). Westernization of diet, partly characterized by excess of long-chain fatty acids, contributes to CD, and a metabolic control of intestinal inflammation is emerging. Here, we report an unexpected inflammatory function for ATG16L1-mediated autophagy in Crohn-like metabolic enteritis of mice induced by polyunsaturated fatty acid (PUFA) excess in a western diet. Dietary PUFAs induce ATG16L1-mediated conventional autophagy in IECs, which is required for PUFA-induced chemokine production and metabolic enteritis. By transcriptomic and lipidomic profiling of IECs, we demonstrate that ATG16L1 is required for PUFA-induced inflammatory stress signaling specifically mediated by TLR2 (toll-like receptor 2) and the production of arachidonic acid metabolites. Our study identifies ATG16L1-mediated autophagy in IECs as an inflammatory hub driving metabolic enteritis, which challenges the perception of protective autophagy in the context of diet westernization.Abbreviations: AA: arachidonic acid; ATG16L1: autophagy related 16 like 1; CD: Crohn disease; CXCL1: C-X-C motif chemokine ligand 1; ER: endoplasmic reticulum; GFP: green fluorescent protein; GPX4: glutathione peroxidase 4; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; PUFA: polyunsaturated fatty acid; SDA: stearidonic acid; TLR2: toll-like receptor 2; WT: wild-type.

Macroautophagy/autophagy is a highly conserved pathway responsible for the bulk degradation of cytoplasmic material through the formation of a double-membrane structure known as the autophagosome. However, the precise mechanisms governing the transport of autophagosomes to the vacuole for degradation in plants remain largely elusive. There exists an ongoing debate about whether RAB7, a key regulatory protein, is involved in the plant autophagy pathway. In this study, we demonstrate that upon autophagy induction by BTH treatment, RABG3e, a member of the RAB7 family, exhibits a partial localization with late-stage autophagosomes in Arabidopsis root cells, and its dysfunction leads to the accumulation of enlarged multilayered autophagosomes and a significant reduction in autophagic flux. We also showed that RABG3e is recruited to autophagosomes by its guanine nucleotide exchange factor (GEF) complex, MON1-CCZ1, which is targeted through the interaction between CCZ1 and SH3P2 (SH3 DOMAIN-CONTAINING PROTEIN 2), a plant-specific autophagy regulator. Subsequently, RABG3e recruits downstream effectors such as VPS39, which in turn promotes the recruitment of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) proteins, including SYP21, VTI12, SYP51, and VAMP711, that are essential for the fusion process. Arabidopsis mutants with dysfunction in the autophagosome-vacuole fusion process exhibit accelerated senescence and increased sensitivity to nitrogen starvation. Collectively, our findings provide new insights into the regulation of autophagosome-vacuole fusion in Arabidopsis, highlighting the essential roles of SH3P2-dependent targeting of the CCZ1-MON1-RABG3e module to late-stage autophagosomes as well as RABG3e effectors and a unique SNARE complex.

N/A.