GCN5L1/BLOS1 Links Acetylation, Organelle Remodeling, and Metabolism

Abstract

General control of amino acid synthesis 5 (GCN5) like-1 (GCN5L1) was identified as a novel gene with sequence homology to the histone acetyltransferase Gcn5. Subsequent protein-interaction studies identified GCN5L1 as a subunit of the multiprotein lysosome biogenesis complex, resulting in an alternative designation as biogenesis of lysosome-related organelle complex 1 subunit 1 (BLOS1 or BLOC1S1). Despite the distinct nomenclatures, GCN5L1/BLOS1 has been shown to play crucial roles in mitochondria, endosomes, lysosomes, and synaptic vesicle precursors (SVPs). GCN5L1/BLOS1 controls mitochondrial protein acetylation, modulates metabolic pathways, and orchestrates retrograde mitochondria-to-nucleus signaling. It also contributes to endosome-lysosome and vesicle trafficking and to endolysosomal function. Here we discuss the intracellular roles of GCN5L1/BLOS1 in the hope of linking mitochondria-centric effects to cytosolic vesicle biology.

Keywords: BORC complex; endosomal function; lysosome trafficking; mitochondria; retrograde signaling.

Figure 1. Schematic of Proposed Functions of Mitochondrial GCN5L1

A. In mouse embryonic fibroblasts (MEFs) and transformed cell lines, the genetic depletion of GCN5L1 reduced mitochondrial protein acetylation in parallel with induction of mitochondrial biogenesis (PGC-1α) and lysosomal biogenesis (TFEB) regulatory programs. This effect is postulated to result from retrograde signaling from the michondria to nucleus, although the signaling pathway have not been defined. B. The role of mitochondrial signaling from the disruption of GCN5L1 levels was further expanded upon in the regulation of transcriptional regulation of gluconeogenesis. Here, in primary hepatocytes, the genetic depletion of GCN5L1 increased mitochondrial ROS-driven ERK signaling which promoted FoxO1 degradation and the subsequent downregulation in hepatic gluconeogenesis. C. Physiologic studies showed that during heart development or in response to high fat feedings cardiac GCN5L1 levels were increased and this was linked to increased fatty acid oxidation enzyme acetylation and activity. D. On the outer mitochondrial membrane (OMM) in embryonic stem cells (ESCs) GCN5L1 functions in concert with the acetyl-CoA generating enzyme L-threonine dehydrogenase (TDH) to acetylate a kinesin binding protein (KBP). This modification in turn promoted the proteasomal degradation of KBP via the ubiquitin ligase Fbxo15. In the absence of GCN5L1 the levels of KBP are maintained which drove mitochondrial biogenesis.

Figure 2. The Prokaryotic Xenobiotic Acetyltransferase (XAT) Architecture of GCN5L1 is Highly Conserved in Human Lysine Acetyltransferases

A. Alignment of the streptogramin acetyltransferase from Burkholderiathailandensis (BtXAT) and the short isoform of GCN5L1. The XAT-containing region of GCN5L1 (grey highlight), BtXAT substrate-binding (grey line), BtXAT acetyl-CoA-binding (black line) and XAT repeats (open box) are marked. B. Sequence alignment of GCN5L1 proteins from Homo sapiens, Mus musculus, Bos taurus, Xenopus laevis, Danio rerio, Drosophila melanogaster and Arabidopsis thaliana. The XAT-hexapeptide repeat regions are highlighted by horizontal bars. C. The human HAT1 acetyltransferase core domain contains two XAT repeats (grey highlight) which bracket the conserved motif A. The three motifs of the HAT1 core domain are identified by boxes.

Figure 3. Schematic of Poposed Functions of GCN5L1/BLOS1 in Regulating Endosome-Lysosome Trafficking and Function

A. GCN5L1 interacted with sorting nexin 2 (SNX2) and the endosomal sorting complex required for transport 1 component TSG101 to mediate the sorting of epidermal growth factor receptor (EGFR) into endosomal compartments with its subsequent trafficking to lysomes to facilitate receptor degradation. B. As a component of the BORC complex, GCN5L1 facilitated lysosomal and synaptic vessicule precusor (SVP) trafficking in conjunction with the GTPase Arl8 and interaction with the motor protein Kinesin 1. C. Components of the BORC complex, including GCN5L1 are required to initiate STING orchestrated lysosomal rupture for the downstream activation of the NLRP3 inflammasome.