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Myxococcus Csga, Drosophila Sniffer, and Human HSD17B10 Are Cardiolipin Phospholipases

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Myxococcus Csga, Drosophila Sniffer, and Human HSD17B10 Are Cardiolipin Phospholipases Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Myxococcus CsgA, Drosophila Sniffer, and human HSD17B10 are cardiolipin phospholipases Tye O’Hara Boynton and Lawrence Joseph Shimkets Department of Microbiology, University of Georgia, Athens, Georgia 30602, USA Myxococcus xanthus development requires CsgA, a member of the short-chain alcohol dehydrogenase (SCAD) family of proteins. We show that CsgA and SocA, a protein that can replace CsgA function in vivo, oxidize the 2′-OH glycerol moiety on cardiolipin and phosphatidylglycerol to produce diacylglycerol (DAG), dihydroxyacetone, and orthophosphate. A lipid extract enriched in DAGs from wild-type cells initiates development and lipid body pro- duction in a csgA mutant to bypass the mutational block. This novel phospholipase C-like reaction is widespread. SCADs that prevent neurodegenerative disorders, such as Drosophila Sniffer and human HSD17B10, oxidize car- diolipin with similar kinetic parameters. HSD17B10 exhibits a strong preference for cardiolipin with oxidized fatty acids. This activity is inhibited in the presence of the amyloid β peptide. Three HSD17B10 variants associated with neurodegenerative disorders are inactive with cardiolipin. We suggest that HSD17B10 protects humans from reac- tive oxygen species by removing damaged cardiolipin before it induces apoptosis. [Keywords: Myxococcus xanthus; CsgA; Drosophila Sniffer; HSD10; phospholipase; cardiolipin] Supplemental material is available for this article. Received July 8, 2015; revised version accepted August 17, 2015. Myxococcus xanthus displays a unique multicellular life- In the current model for extracellular complementation style when faced with amino acid limitation. Cells move of csgA mutants, often referred to as C-signaling, full- in travelling waves or ripples (Shimkets and Kaiser length p25 (kilodalton) CsgA is processed to a p17 form 1982), form evenly spaced multicellular aggregates known that is exported to the cell surface where it binds a recep- as fruiting bodies (Xie et al. 2011), and differentiate into tor on an adjacent cell (Lobedanz and Sogaard-Andersen dormant spores within these aggregates (Holkenbrink 2003). Proteolytic processing of CsgA is mediated by ser- et al. 2014). Several differentiating cell types are produced, ine protease PopC, and a popC mutant has abrogated de- leading to programmed cell death (PCD), sporulation, and velopment (Rolbetzki et al. 2008). However, the current production of peripheral rods (O’Connor and Zusman model fails to account for many critical pieces of data 1991; Boynton et al. 2013). Some mutations that abolish that are inconsistent with it. For example, CsgA has fea- multicellular development can be transiently restored in tures associated with enzymatic function, such as a Ross- the presence of wild-type cells (Hagen et al. 1978). Extra- mann fold, shown to bind NAD+ in vitro, and conserved cellular complementation is due to either intercellular catalytic residues typical of short-chain alcohol dehydro- signaling or metabolic cross-feeding. genases (SCADs), shown to be essential for development Perhaps the most interesting extracellular comple- in vivo (Lee et al. 1995). Membrane fractionation indicat- mentation group is produced by loss of the csgA gene ed that CsgA is an inner membrane protein (Simunovic (MXAN_RS06255), which fully eliminates development et al. 2003), not an outer membrane protein as previously (Hagen and Shimkets 1990). Increasing levels of csgA ex- reported (Lobedanz and Sogaard-Andersen 2003). Exten- pression induce successive developmental behaviors (Li sive proteomic studies have likewise never placed CsgA et al. 1992). Low expression levels (10%–20% of final in the outer membrane or on the cell surface (Kahnt developmental levels) induce rippling. Higher levels of et al. 2010; Bhat et al. 2011), and no receptor has ever expression then entrain cell aggregation into fruiting bod- been identified. The p17 form lacks the N-terminal ies. Sporulation is achieved when csgA is expressed at the NAD+-binding domain, and genomic replacement of a peak concentration, completing the developmental pro- truncated csgA gene encoding an 18.1-kDa protein abol- gram. Addition of exogenous, purified CsgA can restore ishes development (Lobedanz and Sogaard-Andersen aggregation at low concentrations and sporulation at high- er concentrations (Kim and Kaiser 1991). © 2015 Boynton and Shimkets This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/ Corresponding author: [email protected] terms.xhtml). After six months, it is available under a Creative Commons Article published online ahead of print. Article and publication date are License (Attribution-NonCommercial 4.0 International), as described at online at http://www.genesdev.org/cgi/doi/10.1101/gad.268482.115. http://creativecommons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 29:1–12 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/15; www.genesdev.org 1 Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Boynton and Shimkets 2003). Finally, up-regulation of SocA, a distantly related phatidylglycerol (PG). The enzymatic product is unstable homolog of CsgA with only 28% amino acid identity, re- and fragments into diacylglycerol (DAG), dihydroxyace- stores development (Lee and Shimkets 1994, 1996). Since tone (DHA), and orthophosphate (Pi). We propose that SocA must be substantially up-regulated to rescue devel- developing Myxococcus cells use this reaction to con- opment in vivo, it was suggested that rescue is due to vert phospholipids into triacylglycerol (TAG) as the cells SocA having substrate overlap. SocA was shown to oxidize shorten during sporulation. Drosophila and humans in- the phospholipid lysophosphatidylethanolamine (lyso-PE) stead use this reaction to remove damaged CL before it in vitro (Avadhani et al. 2006). causes apoptosis. CsgA homologs are found in eukaryotes, and genetic studies have provided compelling evidence that they pre- vent neurodegenerative disorders. A unifying feature of Results these neurodegenerative disorders is a marked increase Expression and purification of CsgA yields in reactive oxygen species (ROS) (Cobb and Cole 2015). an active enzyme Lipid peroxyl radicals are among the most dangerous prod- ucts of ROS, since they autocatalyze their own production To facilitate production of p25 CsgA, the csgA gene (Gardner 1989). Once a lipid radical is formed, it perpetu- (MXAN_RS06225; MXAN_1294) was codon-optimized ates production by creating a new radical on a neighboring for Escherichia coli (Supplemental Fig. S1) and cloned fatty acid at the site of bis-allylic hydrogens. Formation of with an N-terminal six-histidine tag. For the p17 form, new radicals terminates only when two radicals react to only the 168 C-terminal codons were used. Purified re- produce a fatty acyl peroxide. An insertion in the csgA ho- combinant protein (Supplemental Fig. S2A) rescues csgA molog sniffer from Drosophila produces oxidative stress- mutant (LS2442) development to produce spore-filled related neurodegeneration that includes enhanced apo- fruiting bodies comparable in size and number with those ptosis and reduced locomotor fitness (Botella et al. produced by wild-type DK1622 cells (Supplemental Fig. 2004). Sniffer can reduce a byproduct of lipid peroxidation, S2B). Our p17 failed to restore development in the same (E)-4-oxonon-2-enal (4ONE), to (E)-4-hydroxynon-2-enal assay. (4HNE) in vitro, which is less neurotoxic (Martin et al. Enzymatic activity of the recombinant enzyme was ex- 2011). However, 4HNE is still a potent electrophile with amined with a modified version of the SocA assay (Avad- deleterious effects on proteins and nucleic acids, suggest- hani et al. 2006). Since a known substrate of SocA is lyso- ing that Sniffer has another role in neuroprotection. PE, whole-cell lipids were extracted with chloroform and Another interesting CsgA homolog is the human SCAD methanol. This extract was used as a CsgA substrate, 17β-hydroxysteroid dehydrogenase type 10 (HSD10), the and activity was measured as the conversion of NAD+ to product of the HSD17B10 gene located on chromosome NADH (Fig. 1A). CsgA displays enzymatic activity in the Xp11.2. HSD10 is imported into the mitochondria by a presence of these lipids. Removal of exogenous NAD+ re- pathway involving Parkin, a protein whose function is ab- sulted in a small amount of observed activity, presumably rogated in patients with Parkinson’s disease (Bertolin due to copurified NAD+. No activity is generated unless et al. 2015). A wide variety of enzymatic activities have the enzyme is present. As expected, p17 CsgA displays been associated with HSD10 (Yang et al. 2014), and their no activity in this assay, since it lacks the NAD+-binding clinical significance has been examined extensively. Mu- domain. As an additional negative control, CsgA bearing tations in the HSD17B10 gene have been reported in 19 the active site mutation K155R (Lee et al. 1995) was exam- families (Zschocke 2012). In the classical infantile form ined and is inactive. Enzymatic reactions with CsgA did of the disease caused by mutation p.R130C, symptoms not take place in the presence of NADP+ (Supplemental emerge ∼6–18 mo after birth, and males show progressive Fig. S3), unlike SocA, which was previously
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