Thursday, April 3, 2025
4/3/2025
ATase1 and ATase2, proteostasis, and neurological diseases - We discovered that Nε-lysine acetylation occurs in the lumen of the endoplasmic reticulum (ER) in 2007. From that initial finding, we went on to discover the entire ER acetylation machinery (one membrane transporter, AT-1/SLC33A1, and two acetyltranferases, ATase1 and ATase2) and uncover a novel piece of ER biology. Specifically, we discovered that the ER acetylation machinery regulates proteostasis within the secretory pathway as well as metabolic crosstalk between different intracellular organelles and compartments. Human-based studies discovered that dysfunctional ER acetylation, as caused by loss-of-function homozygous and heterozygous mutations or gene duplication events, is associated with different human diseases, from developmental delay of the brain and premature death to peripheral forms of neuropathy, autism spectrum disorder, intellectual disability and segmental progeria. Mouse models that mimic these genetic events recapitulate associated human diseases. Importantly, ATase-targeting compounds that restore the proteostatic functions of the ER rescue the disease phenotypes of the animals. In conclusion, we have identified a novel molecular machinery that is key to the maintenance of proteostasis within the secretory pathway, and that can be targeted to (i) understand the pathophysiology of several related neurological diseases and (ii) develop appropriate translational approaches to resolve proteostatic defects. The GENERAL HYPOTHESIS of this research is that ATase1 and ATase2 act downstream of an intracellular communication network that regulates the proteostatic functions of the ER and secretory pathway. Our main goal is to dissect the molecular mechanism(s) underlying the acetyl-CoA:lysine acetyltransferase activity of the ATases and understand how ER-based acetylation regulates the efficiency of the secretory pathway. Aim 1 will test the hypothesis that the ATases have divergent functions and differentially regulate proteostasis and metabolic crosstalk. Aim 2 will test the hypothesis that unique structural features allow the ATases to respond to acetyl-CoA influx, Ca++ levels, and perturbations in ER proteostasis. Aim 3 will test the hypothesis that the acetyl group added in the ER lumen by the ATases must be removed in the lumen of the Golgi apparatus by Amfion/GDAC to ensure correct trafficking of nascent glycoproteins and the quality of the secretome. In conclusion, this proposal is based on novel findings from our laboratory and offers a series of highly mechanistic studies that have the potential to define new avenues of research (and treatment) for different neurological diseases. The proposal will use unique mouse models as well as highly integrated novel experimental approaches. We believe that upon completion of these studies, we will have defined an entirely new avenue of research for different neurological diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).