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Endoplasmic Reticulum Acyltransferase with Prokaryotic Substrate Preference Contributes to Triacylglycerol Assembly in Chlamydomonas

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Endoplasmic Reticulum Acyltransferase with Prokaryotic Substrate Preference Contributes to Triacylglycerol Assembly in Chlamydomonas Endoplasmic reticulum acyltransferase with prokaryotic substrate preference contributes to triacylglycerol assembly in Chlamydomonas Yeongho Kima,b, Ee Leng Ternga,b, Wayne R. Riekhofa, Edgar B. Cahoonb,c, and Heriberto Ceruttia,b,1 aSchool of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588; bCenter for Plant Science Innovation, University of Nebraska-Lincoln, Lincoln, NE 68588; and cDepartment of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588 Edited by Krishna K. Niyogi, Howard Hughes Medical Institute and University of California, Berkeley, CA, and approved January 3, 2018 (received for review September 9, 2017) Understanding the unique features of triacylglycerol (TAG) metab- transferase (PDAT), are also consistent with TAG assembly tak- olism in microalgae may be necessary to realize the full poten- ing place in the ER (11–13). tial of these organisms for biofuel and biomaterial production. In In contrast, in C. reinhardtii, TAGs accumulated under nitro- the unicellular green alga Chlamydomonas reinhardtii a chloro- gen deprivation mostly have C16 at their sn-2 position and it has plastic (prokaryotic) pathway has been proposed to play a major been hypothesized that the plastidial pathway plays a major role in role in TAG precursor biosynthesis. However, as reported here, C. TAG synthesis (4, 14, 15). Since a canonical, ER-targeted LPAAT reinhardtii contains a chlorophyte-specific lysophosphatidic acid was not identified in the C. reinhardtii genome (16), the plas- acyltransferase, CrLPAAT2, that localizes to endoplasmic reticulum tidial chlorophyte-specific (Cr)LPAAT1 has been suggested to (ER) membranes. Unlike canonical, ER-located LPAATs, CrLPAAT2 participate actively in generating precursors for TAG accumula- prefers palmitoyl-CoA over oleoyl-CoA as the acyl donor sub- tion (15). Moreover, light and electron microscopy revealed LDs strate. RNA-mediated suppression of CrLPAAT2 indicated that the in both the cytosol and the chloroplast of nutrient-starved C. rein- enzyme is required for TAG accumulation under nitrogen depri- hardtii, although plastid-located large LDs were observed only in vation. Our findings suggest that Chlamydomonas has a distinct starchless mutants deprived of nitrogen under mixotrophic con- glycerolipid assembly pathway that relies on CrLPAAT2 to gener- ditions or in wild-type strains under special environmental con- ate prokaryotic-like TAG precursors in the ER. ditions such as saturating light (17, 18). These findings, together with the predicted subcellular location of major enzymes of TAG LPAAT j lipid droplets j triacylglycerol metabolism j algae j biofuels biosynthesis (3, 4), support the involvement of both the prokary- otic and eukaryotic pathways in algal TAG assembly, but their riacylglycerol (TAG) is a major storage lipid in most eukary- contributions may vary depending on cultivation conditions and Totes and a precursor for biodiesel production (1, 2). Some strain genotype. Additionally, LPAATs have not been character- microalgae have recently gained attention because they can accu- ized in detail in microalgae and it is not certain that the plant mulate large amounts of TAGs and potentially serve as feedstock paradigm regarding LPAAT substrate specificity in the two path- for biofuel production (2–4). However, despite current advances, ways applies universally to algal species. our understanding of algal lipid metabolism is still fairly lim- Here we demonstrate that C. reinhardtii contains a unique ited and generally based on insights from land plants, even for LPAAT, encoded by Cre17.g738350 and termed CrLPAAT2, the well-studied model system Chlamydomonas reinhardtii (3, which seems to be restricted to the chlorophytes. CrLPAAT2 is 4). However, algal metabolism appears to have some distinct localized to the ER but, like prokaryotic acyltransferases, prefers features (4, 5) whose understanding may be required for the C16:0-CoA over C18:1-CoA as the substrate. RNA-mediated biotechnological improvement of algal strains. During the biogenesis of complex lipids in plants, fatty acids Significance synthesized de novo in the chloroplast can be assembled into glycerolipids by the prokaryotic (plastidial) pathway or they The acyl chain composition of Chlamydomonas triacylglyc- can be exported to the endoplasmic reticulum (ER), entering erols (TAGs) suggests that they are assembled from prokary- the eukaryotic pathway of glycerolipid assembly. Glycerolipids otic precursors, proposed to be synthesized in the chloroplast. synthesized by the prokaryotic pathway carry a 16-carbon acyl However, in most eukaryotes, the endoplasmic reticulum (ER) chain at the sn-2 position of the glycerol backbone, whereas appears to be the main organelle for storage TAG biosyn- glycerolipids assembled by the eukaryotic pathway contain an thesis. Interestingly, Chlamydomonas reinhardtii has a dis- 18-carbon acyl chain at the same position (6). This distinc- tinct lysophosphatidic acid acyltransferase that localizes to the tion is caused by differences in the substrate specificity of ER but resembles prokaryotic lysophosphatidic acid acyltrans- lysophosphatidic acid acyltransferases (LPAATs). Chloroplast- ferases (LPAATs) in its substrate preference. Thus, Chlamy- localized LPAATs mainly use palmitoyl-ACP (C16:0-ACP) domonas and related green algae, unlike land plants, can as the acyl donor to generate sn-2-C16:0-phosphatidic acid synthesize “prokaryotic” acyl-lipids in the ER, with intriguing (PA) (7, 8) while those in the ER prefer using oleoyl- implications for biotechnological applications. CoA (C18:1-CoA) to synthesize sn-2-C18:1-PA (9, 10). These observations have been recapitulated in numerous land plants Author contributions: Y.K. and H.C. designed research; Y.K. and E.L.T. performed (7–11). research; Y.K., E.L.T., W.R.R., E.B.C., and H.C. analyzed data; and Y.K. and H.C. wrote the In plant seeds, the assembly of storage TAGs occurs in the paper. ER, having C18 esterified at the sn-2 position of their glycerol The authors declare no conflict of interest. backbone (11). Moreover, in plants, mammals, and fungi, micro- This article is a PNAS Direct Submission. scopic observations of TAG-containing lipid droplets (LDs) Published under the PNAS license. and the subcellular location of major enzymes involved in the 1 To whom correspondence should be addressed. Email: [email protected]. final step of TAG synthesis, such as acyl-CoA:diacylglycerol This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. acyltransferases (DGATs) and phospholipid:diacylglycerol acyl- 1073/pnas.1715922115/-/DCSupplemental. 1652–1657 j PNAS j February 13, 2018 j vol. 115 j no. 7 www.pnas.org/cgi/doi/10.1073/pnas.1715922115 Downloaded by guest on September 28, 2021 silencing of CrLPAAT2 indicated that the enzyme is required A for TAG accumulation under nitrogen deprivation in photoau- totrophic conditions. Thus, Chlamydomonas (and related green algae) appears to rely on CrLPAAT2 to generate prokaryotic- like TAG species in the ER. Results B Substantial TAG accumulation is triggered by nutritional stress in many microalgae (2, 19). However, somewhat unexpect- edly, systems-level approaches revealed that nitrogen-depleted Chlamydomonas showed up-regulation of few genes involved in acyl-lipid metabolism (20–22). Moreover, several genes pre- sumably involved in de novo fatty acid synthesis appeared to be down-regulated under these conditions, despite an increased carbon flux toward TAG biosynthesis (14). The transcript abun- dance of Cre17.g738350, encoding CrLPAAT2, remained rel- atively stable under nitrogen deprivation in mixotrophic con- ditions (20, 21) but increased slightly (see below) under the same stress in photoautotrophic conditions. Despite this mod- est change in gene expression, given some distinctive features of the predicted CrLPAAT2 enzyme, we decided to investigate its role in acyl-lipid metabolism under nutritional deprivation. CrLPAAT2 Has Unique Structural Features and Belongs to a Chloro- phyte-Specific Clade. The predicted amino acid sequence of Cre17.g738350, like conventional LPAATs, contains a LPAAT/ AGPAT domain (PANTHER10434) identified by the Inter- proScan program. ChloroP and PredAlgo algorithms suggested that CrLPAAT2 does not have a chloroplast transit peptide (Fig. 1A and SI Appendix, Table S1). However, analyses of transmembrane domains (TMs) by TMHMM (transmembrane hidden Markov model) and of catalytic sites by InterproScan revealed that the N-terminal half of CrLPAAT2 is fairly sim- ilar to the central region of chloroplast LPAATs (8, 15) (Fig. C 1A and SI Appendix, Fig. S1). In contrast, the C-terminal half of CrLPAAT2 contains two predicted TMs, a structure simi- PLANT BIOLOGY lar to that of eukaryotic LPAATs such as AtLPAT2 from Ara- bidopsis thaliana and LAT1 from Limnanthes douglasii (9, 23) (Fig. 1A and SI Appendix, Fig. S1). Indeed, CrLPAAT2 seems to have a chimeric structure, combining domains from plastidial and eukaryotic LPAATs. To gain insight into the evolutionary origin of CrLPAAT2, Fig. 1. Schematic diagrams of LPAATs and subcellular localization of phylogenetic analyses were performed with available LPAAT- CrLPAAT2. (A) Schematic protein diagrams indicating key domains: chloro- related algal sequences and those from assorted eukaryotes plast transit peptide (red), LPAAT catalytic domain (black), and transmem- and eubacteria (SI Appendix, Fig. S2). Interestingly, CrLPAAT2 brane domains (gray). (B) Subcellular localization of
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