Biology subjects

Kwon, Y. T.

Publications and source records attributed to Kwon, Y. T..

6 recordsLinked to original sources

bioRxiv2026

AUTOTAC-mediated targeted degradation of transthyretin aggregates ameliorates hereditary transthyretin amyloidosis

Hereditary transthyretin amyloidosis (hATTR) is characterized by extracellular deposition of amyloidogenic transthyretin (TTR) aggregates, yet the mechanisms governing their clearance remains poorly understood. Here, we identify a key role for the N-degron pathway in lysosomal degradation of the pathogenic TTRV30M variant. Misfolded intracellular TTRV30M was rapidly secreted and subsequently re-entered within 24 hours during cell-to-cell trafficking. The molecular chaperone R-BiP--N-terminally (Nt) arginylated HSPA5/BiP/GRP78-- associated with intracellular TTRV30M, and its Nt-arginine functioned as an agonist for the N-recognin sequestosome 1 (SQSTM1/p62). This interaction facilitated p62-dependent autophagosomal sequestration and lysosomal degradation of TTRV30M. To pharmacologically exploit this mechanism, we applied the AUTOTAC (AUTOphagy-TArgeting Chimera) platform, which enables the targeting of substrates to p62 for autophagic clearance. We developed Autotac 201 (ATC201), an 876-Da chimera designed to bind both the T4 pocket of aggregated TTR and p62, thereby promoting selective autophagic degradation. In cultured cells, ATC201 potently reduced intracellular TTRV30M aggregates in a manner depending on p62-mediated autophagy, exhibiting a DC of low nM. In hATTR model mice, ATC201 markedly lowered tissue TTR aggregate burden and restored autophagy pathway flux impaired by aggregate accumulation. Treatment improved nerve conduction parameters and reduced peripheral neuropathy scores, indicating functional rescue. ATC201 also led to preservation of muscle strength and attenuation of systemic amyloid deposition. Our findings reveal that the N-degron pathway orchestrates autophagic removal of TTR aggregates and demonstrate the therapeutic potential of AUTOTAC-based degraders for hATTR and other proteinopathies characterized by pathogenic protein aggregation.

cell biology↗

bioRxiv2026

Chemical activation of mitophagy via the N-degron pathway alleviates mitochondrial neuropathies

Pharmacological activation of mitophagy offers a promising strategy to eliminate dysfunctional mitochondria. We previously identified the autophagy receptor p62/SQSTM1 as an N-recognin whose activity is enhanced by Arg/N-degrons. Here, we show that Arg/N-degrons generated by ATE1-encoded R-transferase regulate p62-mediated mitophagy by promoting its recruitment to damaged mitochondria. Structural modification of Arg/N-degrons yielded ATB1071, a 443.5-Da orally bioavailable compound that activates p62 and induces stress-selective mitophagy through both Parkin-independent pathways involving NIPSNAP1 and NIPSNAP2, and a Parkin-dependent pathway involving the substrate EBP1/PA2G4. In Ndufs4-/- mice, a Leigh syndrome (LS) model, ATB1071 induced mitophagy in the brain and exerted therapeutic benefits by reducing neuroinflammation, improving muscle strength and neuromuscular coordination, and extending lifespan. In cerebral ischemia-reperfusion (IR) model mice, ATB1071 reduced infarct volume and neuronal death, and ameliorated multiple behavioral deficits through EBP1-dependent mitophagy. Pharmacokinetic (PK) and toxicological analyses support ATB1071 as a preclinical candidate for mitochondria-associated neurological injury.

cell biology↗

bioRxiv2025

Targeted degradation of pathologic tau aggregates via AUTOTAC ameliorates tauopathy

The pathogenesis of tauopathies including Alzheimers disease (AD) and progressive supranuclear palsy (PSP) involves the misfolding and aggregation of tau. Here, we employed AUTOTAC to induce the lysosomal degradation of intraneuronal tau aggregates. ATB2005A is a 734-Da chimera that simultaneously binds {beta}-sheet-rich tau aggregates and the autophagic receptor p62/SQSTM1, leading to autophagosomal sequestration and lysosomal co-degradation. In mouse models of tauopathies, orally administered ATB2005A lowered intraneuronal tau aggregates and exerted the therapeutic efficacy in neuroinflammation as well as cognition, behavior, and muscle movements. A Phase 2 clinical trial (U34401-4/2023/14) with companion dogs carrying canine cognitive dysfunction (CCD) demonstrated the efficacy of ATB2005A, as a veterinary medicine, to reverse the disease progression. ATB2005A is under Phase 1 clinical trial with human participants in Korea (202300697). These results validate AUTOTAC as a versatile platform for developing therapeutics to eradicate toxic protein aggregates in a wide range of proteinopathies.

neuroscience↗

bioRxiv2025

Targeted degradation of pathogenic TDP-43 proteins in amyotrophic lateral sclerosis using the AUTOTAC platform

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons and the cytoplasmic aggregation of misfolded proteins in the spinal cord, including TAR DNA-binding protein-43 (TDP-43). More than 97% of ALS cases exhibit pathological TDP-43 inclusions, yet therapeutic strategies that can selectively eliminate these aggregates remain yet to be developed. Here, we employed the AUTOTAC (Autophagy-Targeting Chimera) to degrade TDP-43 aggregates via macroautophagy mediated by the N-recognin p62/SQSTM1 of the N-degron pathway. The AUTOTAC degraders ATC141 and ATC142 were designed to bind and link the oligomeric species of misfolded TDP-43 to p62, which induces the targeting of TDP-43 cargoes to phagophores for lysosomal co-degradation, while sparing monomeric TDP-43. ATC142 induced the degradation of pathological TDP-43 A315T species and its cleaved variant, TDP-25, with DC50 values of 1.25-9.6 nM. In ALS model mice expressing TDP-43 A315T in the spinal cord, oral administration of 10 mg/kg ATC141 with 24 doses reduced TDP-43 aggregates as well as GFAP+ astrocytes and Iba1+ microglia. ATC141 also exerted disease-modifying efficacy to reverse the disease progression in neuromuscular coordination and cognitive function. This oral drug is under Phase 1 clinical trials in South Korea with 76 healthy volunteers aiming to treat ALS, Alzheimers diseases (AD), and progressive supranuclear palsy (PSP). We suggest that AUTOTAC provides a novel strategy to treat a broad range of neurodegenerative diseases. TeaserAUTOTAC degraders induce lysosomal degradation of pathogenic TDP-43 aggregates in a mouse model of amyotrophic lateral sclerosis.

neuroscience↗

bioRxiv2025

Targeted degradation of SARS-CoV-2 via the autophagy-lysosome system using chemical mimetics of the N-degron pathway

In the N-degron pathway, ATE1 transfers the amino acid L-arginine (L-Arg) from Arg-tRNAArg to N-terminal (Nt) residues of cellular proteins. The resulting Arg/N-degrons bind the autophagic receptor p62/SQSTSM-1/Sequestosome-1 to induce lysosomal degradation of various biomaterials. Here, we demonstrate that the chemical mimetics of Arg/N-degrons, termed autophagy-targeting ligands (ATLs), can induce lysosomal degradation of SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) via p62-mediated macroautophagy. In Vero E6 cells infected with SARS-CoV-2, ATLs promoted p62 self-polymerization and enhanced LC3 synthesis and lipidation, leading to viral sequestration within autophagosomes for lysosomal degradation. In transgenic mice overexpressing human angiotensin-converting enzyme 2 (ACE2), oral administration of ATL1014 inhibited viral replication and increased viability. In a Syrian hamster model, ATL1014 attenuated viral replication in the lungs and demonstrated efficacy in inflammatory lesions and pulmonary congestions. These results identify the N-degron pathway as a potential target for a host-targeting strategy (HTS) against a broad spectrum of viruses.

microbiology↗

bioRxiv2022

ECPAS/Ecm29-Mediated 26S Proteasome Disassembly Is an Adaptive Response to Glucose Starvation

The 26S proteasome consists of loosely associated 20S catalytic and 19S regulatory complexes. Approximately half of the proteasomes in eukaryotic cells exist as free 20S complexes; however, our mechanistic and physiological understanding of what determines the ratio of 26S to 20S species remains incomplete. Here, we show that glucose starvation in mammalian cells results in the uncoupling of 26S holoenzymes into intact 20S and 19S subcomplexes. Subcomplex affinity-purification and quantitative mass spectrometry revealed that Ecm29 proteasome adaptor and scaffold (ECPAS) is a crucial mediator of this structural remodeling. The loss of ECPAS abrogated 26S dissociation, leading to decreased degradation of 20S proteasome substrates such as puromycylated polypeptides and lysine-less cyclin B. In silico modeling analysis suggested that the conformational changes of ECPAS may commence the disassembly process. ECPAS was also essential for proper endoplasmic reticulum stress response and cell survival during glucose starvation. In addition, we evaluated the role of ECPAS in vivo using the mouse xenograft model and observed that glucose-deprived tumor tissues had significantly elevated 20S proteasome levels. Collectively, our results indicate that the 20S-19S disassembly mediated by ECPAS is a novel mechanism adapting global proteolysis to physiological needs and an effective cellular strategy against proteotoxic stress.

biochemistry↗