Fine-tuning acetyl-CoA carboxylase 1 activity through localization: functional genomics reveals a role for the lysine acetyltransferase NuA4 and sphingolipid metabolism in regulating Acc1 activity and localization

Abstract

Acetyl-CoA Carboxylase 1 catalyzes the conversion of acetyl-CoA to malonyl-CoA, the committed step of de novo fatty acid synthesis. As a master regulator of lipid synthesis, acetyl-CoA carboxylase 1 has been proposed to be a therapeutic target for numerous metabolic diseases. We have shown that acetyl-CoA carboxylase 1 activity is reduced in the absence of the lysine acetyltransferase NuA4 in Saccharomyces cerevisiae. This change in acetyl-CoA carboxylase 1 activity is correlated with a change in localization. In wild-type cells, acetyl-CoA carboxylase 1 is localized throughout the cytoplasm in small punctate and rod-like structures. However, in NuA4 mutants, acetyl-CoA carboxylase 1 localization becomes diffuse. To uncover mechanisms regulating acetyl-CoA carboxylase 1 localization, we performed a microscopy screen to identify other deletion mutants that impact acetyl-CoA carboxylase 1 localization and then measured acetyl-CoA carboxylase 1 activity in these mutants through chemical genetics and biochemical assays. Three phenotypes were identified. Mutants with hyper-active acetyl-CoA carboxylase 1 form 1 or 2 rod-like structures centrally within the cytoplasm, mutants with mid-low acetyl-CoA carboxylase 1 activity displayed diffuse acetyl-CoA carboxylase 1, while the mutants with the lowest acetyl-CoA carboxylase 1 activity (hypomorphs) formed thick rod-like acetyl-CoA carboxylase 1 structures at the periphery of the cell. All the acetyl-CoA carboxylase 1 hypomorphic mutants were implicated in sphingolipid metabolism or very long-chain fatty acid elongation and in common, their deletion causes an accumulation of palmitoyl-CoA. Through exogenous lipid treatments, enzyme inhibitors, and genetics, we determined that increasing palmitoyl-CoA levels inhibits acetyl-CoA carboxylase 1 activity and remodels acetyl-CoA carboxylase 1 localization. Together this study suggests yeast cells have developed a dynamic feed-back mechanism in which downstream products of acetyl-CoA carboxylase 1 can fine-tune the rate of fatty acid synthesis.

Evolutionary diversity of the control of the azole response by Tra1 across yeast species

“…2017). NuA4 is also linked to sterol metabolism and eaf1Δ cells display increased accumulation of ergosterol esters (Pham et al . 2022).…”

JAZF1: A metabolic actor subunit of the NuA4/TIP60 chromatin modifying complex

“…As a newly identified subunit of NuA4/TIP60 (Sudarshan et al, 2022), it is unclear if or how JAZF1 regulates enzymatic activity of the complex on or off chromatin. It is especially interesting that the role of NuA4/ TIP60 activity in transcription of metabolic genes and direct regulation of metabolic enzymes is well supported (van Beekum et al, 2008;Lin et al, 2009;Grönniger et al, 2010;Couture et al, 2012;Rossetto et al, 2014;Filteau et al, 2015;Jacquet et al, 2016;Dacquay et al, 2017;Rollins et al, 2017;Li et al, 2018;Cheng et al, 2019;Walden et al, 2020;Liu et al, 2021;Pham et al, 2022). Therefore, it is tempting to speculate that JAZF1 specifically modulates metabolism-related activity of the NuA4/ TIP60 complex.…”

“…First, while JAZF1 suppresses gluconeogenesis (Yuan et al, 2015;Zhou et al, 2020), NuA4/TIP60 is known to promote it (Lin et al, 2009). Second, JAZF1 has a pro-lipolytic anti-lipogenic function (Li et al, 2011;Ming et al, 2014b;Jang et al, 2014;Li et al, 2014;Wei et al, 2018), whereas NuA4/Tip60 was found to positively regulate either lipolysis or lipogenesis in different studies (Dacquay et al, 2017;Rollins et al, 2017;Li et al, 2018;Cheng et al, 2019;Wei et al, 2020;Liu et al, 2021;Pham et al, 2022). Lastly, JAZF1 stimulates the PI3K-Akt pathway downstream of insulin signaling (Yuan et al, 2015;Zhou et al, 2020), but NuA4/TIP60 was found to suppress it (Lu et al, 2011;Yang et al, 2017;Zhang et al, 2018).…”

“…Further, implication of the NuA4/ TIP60 complex in lipid homeostasis is clear, albeit somewhat controversial. In S. cerevisiae, NuA4 subunits Esa1, Eaf1 and Eaf7 promote fatty acid biosynthesis and lipid droplet formation by enhancing activity of the fatty acid biosynthesis enzyme ACC1 (Dacquay et al, 2017;Rollins et al, 2017;Pham et al, 2022). In mammals, there is evidence for Tip60 functioning in the opposing processes of lipogenesis and lipolysis.…”

“…The multisubunit complex NuA4, also known as TIP60 in mammals, is an acetyltransferase that is structurally and functionally conserved across eukaryotes. Composed of 13 proteins in Saccharomyces cerevisiae, of which 12 have homologs in the 18-subunit human complex, including the catalytic subunit Tip60/Esa1 (Doyon et al, 2004;Altaf et al, 2009;Jacquet et al, 2016;Sudarshan et al, 2022) (Supplementary Table S1), NuA4/TIP60 is known to act as a co-activator at metabolic genes (Rossetto et al, 2014;Jacquet et al, 2016), as a direct modulator of metabolic enzymes (Lin et al, 2009;Rollins et al, 2017;Li et al, 2018;Cheng et al, 2019;Pham et al, 2022) and as an effector to metabolic signals that regulate autophagy (Lin et al, 2012;Yi et al, 2012;Cheng et al, 2019;Liu et al, 2021). Intriguingly, recent work has identified JAZF1 as a novel stable subunit of the complex (Piunti et al, 2019;Procida et al, 2021;Alerasool et al, 2022;Sudarshan et al, 2022).…”