PMID- 28487365 OWN - NLM STAT- MEDLINE DCOM- 20170706 LR - 20211204 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 292 IP - 26 DP - 2017 Jun 30 TI - The coccidian parasites Toxoplasma and Neospora dysregulate mammalian lipid droplet biogenesis. PG - 11009-11020 LID - 10.1074/jbc.M116.768176 [doi] AB - Upon infection, the intracellular parasite Toxoplasma gondii co-opts critical functions of its host cell to avoid immune clearance and gain access to nutritional resources. One route by which Toxoplasma co-opts its host cell is through hijacking host organelles, many of which have roles in immunomodulation. Here we demonstrate that Toxoplasma infection results in increased biogenesis of host lipid droplets through rewiring of multiple components of host neutral lipid metabolism. These metabolic changes cause increased responsiveness of host cells to free fatty acid, leading to a radical increase in the esterification of free fatty acids into triacylglycerol. We identified c-Jun kinase and mammalian target of rapamycin (mTOR) as components of two distinct host signaling pathways that modulate the parasite-induced lipid droplet accumulation. We also found that, unlike many host processes dysregulated during Toxoplasma infection, the induction of lipid droplet generation is conserved not only during infection with genetically diverse Toxoplasma strains but also with Neospora caninum, which is closely related to Toxoplasma but has a restricted host range and uses different effector proteins to alter host signaling. Finally, by showing that a Toxoplasma strain deficient in exporting a specific class of effectors is unable to induce lipid droplet accumulation, we demonstrate that the parasite plays an active role in this process. These results indicate that, despite their different host ranges, Toxoplasma and Neospora use a conserved mechanism to co-opt these host organelles, which suggests that lipid droplets play a critical role at the coccidian host-pathogen interface. CI - (c) 2017 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Hu, Xiaoyu AU - Hu X AD - From the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041. FAU - Binns, Derk AU - Binns D AD - From the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041. FAU - Reese, Michael L AU - Reese ML AD - From the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041 michael.reese@UTSouthwestern.edu. LA - eng GR - K22 AI097345/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20170509 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) SB - IM MH - Fibroblasts/*metabolism/parasitology/pathology MH - Host-Parasite Interactions/*physiology MH - Humans MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Lipid Droplets/*metabolism/parasitology/pathology MH - Neospora/*physiology MH - TOR Serine-Threonine Kinases/metabolism MH - Toxoplasma/*physiology MH - Toxoplasmosis/*metabolism/pathology PMC - PMC5491784 OTO - NOTNLM OT - Toxoplasma gondii OT - host-pathogen interaction OT - lipid droplet OT - lipid metabolism OT - parasite COIS- The authors declare that they have no conflicts of interest with the contents of this article EDAT- 2017/05/11 06:00 MHDA- 2017/07/07 06:00 PMCR- 2018/06/30 CRDT- 2017/05/11 06:00 PHST- 2016/11/18 00:00 [received] PHST- 2017/05/05 00:00 [revised] PHST- 2017/05/11 06:00 [pubmed] PHST- 2017/07/07 06:00 [medline] PHST- 2017/05/11 06:00 [entrez] PHST- 2018/06/30 00:00 [pmc-release] AID - S0021-9258(20)36513-3 [pii] AID - M116.768176 [pii] AID - 10.1074/jbc.M116.768176 [doi] PST - ppublish SO - J Biol Chem. 2017 Jun 30;292(26):11009-11020. doi: 10.1074/jbc.M116.768176. Epub 2017 May 9.