Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several degraders that harness the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux is still missing. In this study, we develop a general chemical tool and platform technology termed AUTOphagy-TArgeting Chimera (AUTOTAC), which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands. AUTOTACs bind the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation. We use AUTOTACs to degrade various oncoproteins and degradation-resistant aggregates in neurodegeneration at nanomolar DC50 values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.

Abstract-Diverse cardiac diseases induce cardiac hypertrophy, which leads to dilatation and heart failure. We previously reported that hypertrophy can be blocked by class I histone deacetylase (HDAC) inhibitor, which prompted us to investigate the regulatory mechanism of class I HDACs. Cardiac hypertrophy was introduced by aortic banding, by infusion of isoproterenol or angiotensin II, or by swimming. Hypertrophic stimuli transiently elevated the activity of histone deacetylase-2 (Hdac2), a class I HDAC. In cardiomyocytes, forced expression of Hdac2 simulated hypertrophy in an Akt-dependent manner, whereas enzymatically inert Hdac2 H141A failed to do so. Hypertrophic stimuli induced the expression of heat shock protein (Hsp)70. The induced Hsp70 physically associated with and activated Hdac2. Hsp70 overexpression produced a hypertrophic phenotype, which was blocked either by siHdac2 or by a dominant negative Hsp70⌬ABD. In Hsp70.1 Ϫ/Ϫ mice, cardiac hypertrophy and Hdac2 activation were significantly blunted. Heat shock either to cardiomyocytes or to mice activated Hdac2 and induced hypertrophy. However, heat shock-induced Hdac2 activation was blunted in the cardiomyocytes isolated from Hsp70.1 Ϫ/Ϫ mice. These results suggest that the induction of Hsp70 in response to diverse hypertrophic stresses and the ensuing activation of HDAC2 trigger cardiac hypertrophy, emphasizing HSP70/HDAC2 as a novel mechanism regulating hypertrophy. Key Words: cardiac hypertrophy Ⅲ class I histone deacetylases Ⅲ histone deacetylase 2 Ⅲ heat shock protein 70 Ⅲ Hsp70.1 Ϫ/Ϫ mice C ardiac hypertrophy is a response, either adaptive or maladaptive, to pressure or volume overload, mutations, or loss of contractile mass. Hypertrophic growth accompanies many forms of heart disease, including ischemic diseases, myocardial infarction, hypertension, aortic stenosis, and valvular dysfunctions. Although the initial hypertrophic responses seem to be an adaptation to those stimuli, the sustained stress may lead to cardiomyopathy and heart failure, a major cause of human morbidity and mortality. However, few interventions have proven effective in blocking the hypertrophy or in preventing the transition to congestive heart failure.Cardiomyocyte hypertrophy is characterized by an increase in individual myocyte size, enhanced protein synthesis, and heightened organization of the sarcomere, 1 which are regulated by activation of heart-specific transcription factors such as GATA4, MEF2, and immediate early genes like c-jun and c-fos. 2 The subsequent reactivation of the fetal gene program and repression of adult cardiac genes are closely related to the deterioration of heart function in hypertrophy.Recently, modulation of gene transcription by altering chromatin structure, especially by adding or removing acetyl groups to histone tails, has been implicated in diverse human pathologies, including cardiac hypertrophy. 3 Histone deacetylases (HDACs), which remove the acetyl group, repress downstream gene expression. Although HDACs are divided into 4 familie...