PMID- 30891432 OWN - NLM STAT- MEDLINE DCOM- 20191129 LR - 20200309 IS - 2235-2988 (Electronic) IS - 2235-2988 (Linking) VI - 9 DP - 2019 TI - The Activin Receptor, Activin-Like Kinase 4, Mediates Toxoplasma Gondii Activation of Hypoxia Inducible Factor-1. PG - 36 LID - 10.3389/fcimb.2019.00036 [doi] LID - 36 AB - To grow and cause disease, intracellular pathogens modulate host cell processes. Identifying these processes as well as the mechanisms used by the pathogens to manipulate them is important for the development of more effective therapeutics. As an example, the intracellular parasite Toxoplasma gondii induces a wide variety of changes to its host cell, including altered membrane trafficking, cytoskeletal reorganization, and differential gene expression. Although several parasite molecules and their host targets have been identified that mediate- these changes, few are known to be required for parasite replication. One exception is the host cell transcription factor, hypoxia-inducible factor-1 (HIF-1), which is required for parasite replication in an oxygen-dependent manner. Toxoplasma activates HIF-1 by stabilizing the HIF-1alpha subunit, and this is dependent on the signaling from the Activin-Like Kinase (ALK) receptor superfamily. Here, we demonstrate that specific overexpression of the ALK family member, ALK4, increased HIF-1 activity in Toxoplasma-infected cells, and this increase required ALK4 kinase activity. Moreover, Toxoplasma stimulated ALK4 to dimerize with its co-receptor, ActRII, and also increased ALK4 kinase activity, thereby demonstrating that Toxoplasma activates the ALK4 receptor. ALK4 activation of HIF-1 was independent of canonical SMAD signaling but rather was dependent on the non-canonical Rho GTPase and JNK MAP kinase signaling pathways. Finally, Toxoplasma increased rates of ALK4 ubiquitination and turnover. These data provide the first evidence indicating that ALK4 signaling is a target for a microbial pathogen to manipulate its host cell. FAU - Lis, Agnieszka AU - Lis A AD - Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States. FAU - Wiley, Mandi AU - Wiley M AD - Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States. FAU - Vaughan, Joan AU - Vaughan J AD - Salk Institute, La Jolla, CA, United States. FAU - Gray, Peter C AU - Gray PC AD - Salk Institute, La Jolla, CA, United States. FAU - Blader, Ira J AU - Blader IJ AD - Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States. LA - eng GR - R01 AI069986/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190305 PL - Switzerland TA - Front Cell Infect Microbiol JT - Frontiers in cellular and infection microbiology JID - 101585359 RN - 0 (Hypoxia-Inducible Factor 1) RN - EC 2.7.11.30 (ACVR1B protein, human) RN - EC 2.7.11.30 (Activin Receptors, Type I) SB - IM MH - Activin Receptors, Type I/*metabolism MH - Animals MH - Cells, Cultured MH - *Host-Pathogen Interactions MH - Humans MH - Hypoxia-Inducible Factor 1/*biosynthesis MH - Mice MH - Toxoplasma/*growth & development PMC - PMC6411701 OTO - NOTNLM OT - hypoxia OT - parasite - host interactions OT - tgf-beta signaling OT - toxoplasma and toxoplasmosis OT - transcripional regulation EDAT- 2019/03/21 06:00 MHDA- 2019/11/30 06:00 PMCR- 2019/01/01 CRDT- 2019/03/21 06:00 PHST- 2018/09/14 00:00 [received] PHST- 2019/02/04 00:00 [accepted] PHST- 2019/03/21 06:00 [entrez] PHST- 2019/03/21 06:00 [pubmed] PHST- 2019/11/30 06:00 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fcimb.2019.00036 [doi] PST - epublish SO - Front Cell Infect Microbiol. 2019 Mar 5;9:36. doi: 10.3389/fcimb.2019.00036. eCollection 2019.