1 Cellular Degradation Biology Center, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea. 2 Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea. 3 AUTOTAC Bio Inc., 254, Changgyeonggung-ro, Jongno-gu, Seoul 03077, Republic of Korea. 4 Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea. 5 Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
The prevalence of obesity has increased tremendously, and obesity is regarded as a chronic disease due to a high mortality rate associated with co-morbidities. Intracellular lipid catabolism is achieved by either lipase-based lipolysis or autophagic degradation of lipid droplets called lipophagy. Since N-terminal (Nt)-arginylated proteins have been recently revealed as N-degrons for an autophagic N-recognin, p62, we investigated the role of Nt-arginylation in lipophagy and possible application of Nt-arginylation mimics for obesity and hepatosteatosis. Nt-arginylaed BiP was required to initiate p62-mediated lipophagy, and ablation of the ZZ domain of p62, where arginylated substrates are recognized, abrogated the p62 recruitment to lipid droplets. Furthermore, high fat diet feeding in liver specific Ate1-/- mice caused severe hepatosteatosis compared to wild-type. Finally, Nt-arginylation mimicry was effective in both preventing and alleviating obesity and hepatosteatosis in high fat diet-induced obese mice. The present study suggests Nt-arginylated BiP as an upstream regulator of lipophagy by acting as a degron for p62 oligomerization and activation, and Nt-arginylation mimicry would be clinically applicable for obesity and hepatosteatosis via peripheral lipophagy activation.
Targeting p62 for the treatment of Mycobacterium tuberculosis infection
Abstract
Mycobacterium tuberculosis (Mtb) is a significant causal pathogen of human tuberculosis (TB), a severe health burden worldwide. The demand for developing an innovative therapeutic strategy to treat TB is high due to drug-resistant Mtb strains. Host-directed therapy (HDT) is an emerging therapeutic approach against numerous pathogenic infections. Autophagy is one of the crucial strategies of HDT through activation of a cell-autonomous host defensive mechanism by which intracytoplasmic bacteria can be delivered into and destroyed in lysosomes. Accumulating studies have reported that autophagy/xenophagy-activating agents and small molecules may be beneficial in restricting intracellular Mtb infection. Despite this, there has been a lack in developing xenophagy-inducing drugs with sufficient efficacy and optimal effectiveness against Mtb infection. Previous studies showed that the proteolytic N-degron pathway is interconnected with the autophagic process to promote selective degradation of aberrant target proteins. We have recently found that the synthetic ligands to the autophagic receptor p62/SQSTM1 (p62 ligands) are highly effective in activating autophagy/xenophagy and antimicrobial host defense against infections with Mtb even to multidrug-resistant strain, as well as other intracellular bacteria. These data highlight that the p62 ligands are potentially valuable for host-directed therapy against a broad range of drug-resistant bacteria.
The AUTOTAC (AUTOphagy-TArgeting Chimera) chemical biology platform for targeted protein degradation via the autophagy-lysosome system
Abstract
Proteinopathies are associated with an ever-increasing accumulation of degradation-resistant misfolded hallmark protein aggregates. Traditional approaches for developing ligands that alter the activity of proteinopathy-associated targets are not applicable for pathological aggregates, leaving degraders as possibly the only therapeutic means. Targeted protein degradation allows for targeting undruggable proteins and their aggregates for therapeutic applications as well as eliminating proteins of interest for research purposes. Thus, we developed a general chemical tool by which given intracellular proteins are targeted to macroautophagy for lysosomal degradation. This platform technology, termed AUTOphagy-TArgeting Chimera (AUTOTAC), employs bifunctional molecules composed of target-binding ligands (TBLs) linked to autophagy-targeting ligands (ATLs). The ATL of AUTOTAC compounds binds the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated in complex with targets into oligomeric bodies for their biological inactivation via sequestration, autophagosomal targeting and lysosomal degradation. Since UPS-based degraders are inherently incapable of degrading large oligomers and aggregates due to the size limitations of the proteasome, we tested whether AUTOTACs can target mutant tauP301L that forms neurotoxic and prion-like seed aggregates and neurofibrillary tangles. AUTOTACs selectively degraded oligomers/aggregates of pathological, mutant tau at nanomolar DC50 values. They exerted therapeutic efficacy in eradicating otherwise non-degradable phosphorylated tau oligomers and aggregates from murine brains. The targeted degradation of pathological tau was associated with an improvement in the pathophysiology and behavioral/locomotive decline associated with tauopathies, AUTOTAC provides a platform for selective proteolysis as research tools and in drug development.
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