The endoplasmic reticulum acetyltransferases ATase1/NAT8B and ATase2/NAT8 are differentially regulated to adjust engagement of the secretory pathway. Issue 4 (27th January 2020)

• Record Type: Journal Article
• Authors: Rigby, Michael J.; Ding, Yun; Farrugia, Mark A.; Feig, Michael; Cortese, Giuseppe P.; Mitchell, Heather; Burger, Corinna; Puglielli, Luigi
• Is Part Of: Journal of neurochemistry. Volume 154:Issue 4(2020)
• Page Start: 404
• Page End: 423
• Publication Date: 2020-01-27
• Subjects: acetyltransferase -- ATase1 -- ATase2 -- endoplasmic reticulum -- Nε‐lysine acetylation -- secretory pathway; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14958
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: 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. Abstract : Characterizing the regulation of the endoplasmic reticulum (ER)‐based acetylation machinery can reveal important information regarding its biology and role in neurophysiology. We discovered that one of the two acetyltransferases, ATase1, can be regulated via acetylation. On the other hand, ATase2 was found to be primarily regulated transcriptionally by the immediate‐early gene cascade, and the expression of ATase2 increased following activity‐dependent processes. Finally, both ATase1 and ATase2 modulated the flux of glycoproteins through the secretory pathway. Our results demonstrate mechanistic ways for the cell to regulate the efficiency of the secretory pathway, which has implications in neuron function and beyond.