Endoplasmic reticulum acetyltransferases Atase1 and Atase2 differentially regulate reticulophagy, macroautophagy and cellular acetyl-CoA metabolism.

Autor: Rigby MJ; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.; Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA.; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Lawton AJ; Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA., Kaur G; Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA., Banduseela VC; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA., Kamm WE; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Lakkaraju A; Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA.; Department of Ophthalmology and Anatomy, University of California, San Francisco, CA, USA., Denu JM; Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA., Puglielli L; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA. lp1@medicine.wisc.edu.; Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA. lp1@medicine.wisc.edu.; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA. lp1@medicine.wisc.edu.; Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, WI, USA. lp1@medicine.wisc.edu.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2021 Apr 12; Vol. 4 (1), pp. 454. Date of Electronic Publication: 2021 Apr 12.
DOI: 10.1038/s42003-021-01992-8
Abstrakt: N ε -lysine acetylation in the ER lumen is a recently discovered quality control mechanism that ensures proteostasis within the secretory pathway. The acetyltransferase reaction is carried out by two type-II membrane proteins, ATase1/NAT8B and ATase2/NAT8. Prior studies have shown that reducing ER acetylation can induce reticulophagy, increase ER turnover, and alleviate proteotoxic states. Here, we report the generation of Atase1 -/- and Atase2 -/- mice and show that these two ER-based acetyltransferases play different roles in the regulation of reticulophagy and macroautophagy. Importantly, knockout of Atase1 alone results in activation of reticulophagy and rescue of the proteotoxic state associated with Alzheimer's disease. Furthermore, loss of Atase1 or Atase2 results in widespread adaptive changes in the cell acetylome and acetyl-CoA metabolism. Overall, our study supports a divergent role of Atase1 and Atase2 in cellular biology, emphasizing ATase1 as a valid translational target for diseases characterized by toxic protein aggregation in the secretory pathway.
Databáze: MEDLINE
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