Biology subjects

Sung, K. W.

Publications and source records attributed to Sung, K. W..

4 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↗

bioRxiv2025

Lysosomal swelling triggers LRRK2 activity

LRRK2 is implicated in lysosomal functions, but the physiological upstream cues that engage endogenous LRRK2 activity are incompletely defined. Here we show that lysosomal swelling serves as a selective and reversible trigger for LRRK2-mediated Rab phosphorylation, without requiring membrane damage. Acute inhibition of PIKfyve, but not the general disruption of phosphoinositide signaling, induces the robust accumulation of phosphorylated Rabs across endolysosomal membranes. Rescue of swelling through pharmacological restoration of lysosomal ionic imbalances from PIKfyve inhibition suppresses LRRK2 activation without restoring lysosomal function. Mechanical lysosomal swelling from indigestible osmolyte uptake causes a dose-dependent increase in LRRK2-mediated Rab phosphorylation on both swollen and non-swollen lysosomes. Together, these findings identify LRRK2 as a sensor of lysosomal volume and mechanical stress, not specifically membrane damage or PIKfyve inhibition. As lysosomal swelling is a shared pathological feature across LRRK2-linked diseases, these results reframe LRRK2 as part of an endolysosomal surveillance system responsive to lysosomal distension.

neuroscience↗

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 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↗