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The endoplasmic reticulum acetyltransferases ATase1/NAT8B and ATase2/NAT8 are differentially regulated to adjust engagement of the secretory pathway
Author(s) -
Rigby Michael J.,
Ding Yun,
Farrugia Mark A.,
Feig Michael,
Cortese Giuseppe P.,
Mitchell Heather,
Burger Corinna,
Puglielli Luigi
Publication year - 2020
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14958
Subject(s) - endoplasmic reticulum , acetylation , biology , microbiology and biotechnology , phenotype , gene , unfolded protein response , regulation of gene expression , gene expression , secretory protein , biochemistry
Nε‐lysine acetylation of nascent glycoproteins within the endoplasmic reticulum (ER) lumen regulates the efficiency of the secretory pathway. The ER acetylation machinery consists of the membrane transporter, acetyl‐CoA transporter 1 (AT‐1/SLC33A1), and two acetyltransferases, ATase1/NAT8B and ATase2/NAT8. Dysfunctional ER acetylation is associated with severe neurological diseases with duplication of AT‐1/SLC33A1 being associated with autism spectrum disorder, intellectual disability, and dysmorphism. Neuron‐specific AT‐1 over‐expression in the mouse alters neuron morphology and function, causing an autism‐like phenotype, indicating that ER acetylation plays a key role in neurophysiology. As such, characterizing the molecular mechanisms that regulate the acetylation machinery could reveal critical information about its biology. By using structure‐biochemistry approaches, we discovered that ATase1 and ATase2 share enzymatic properties but differ in that ATase1 is post‐translationally regulated via acetylation. Furthermore, gene expression studies revealed that the promoters of AT‐1 , ATase1 , and ATase2 contain functional binding sites for the neuron‐related transcription factors cAMP response element‐binding protein and the immediate‐early genes c‐FOS and c‐JUN, and that ATase1 and ATase2 exhibit additional modes of transcriptional regulation relevant to aging and Alzheimer's disease. In vivo rodent gene expression experiments revealed that Atase2 is specifically induced following activity‐dependent events. Finally, over‐expression of either ATase1 or ATase2 was sufficient to increase the engagement of the secretory pathway in PC12 cells. Our results indicate important regulatory roles for ATase1 and ATase2 in neuron function with induction of ATase2 expression potentially serving as a critical event that adjusts the efficiency of the secretory pathway for activity‐dependent neuronal functions.