Acidification Activates Motility and Egress by Enhancing Protein Secretion and Cytolytic Activity

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Toxoplasma and related parasites including those that cause malaria are obligate intracellular pathogens that replicate within a specialized compartment termed the parasitophorous vacuole. To infect new host cells these parasites must first escape from the parasitophorous vacuole and other limiting membranes of the currently infected cell. Escape, or egress as it is often called, depends on the timely release of adhesive proteins and lysis factors from secretory organelles called micronemes. Although this secretory event is crucial for egress, the natural environmental cues that trigger microneme secretion remain poorly defined. Here we discover that acidification of the parasitophorous vacuole is sufficient to trigger microneme secretion and promote the activity of a lysis factor called PLP1. We also show that pH-neutralizing drugs inhibit egress and provide evidence of parasitophorous vacuole acidification approximately coinciding with parasite egress from infected host cells. The findings support a working model in which acidification activates microneme dependent motility and lytic activity to execute egress and destruction of infected cells. The results also provide insight into how PLP1 lytic activity is stimulated during egress in an acidic environment and subsequently suppressed by the neutral extracellular environment, thus permitting cell invasion with minimal damage to the next target cell.

Vyšlo v časopise: Acidification Activates Motility and Egress by Enhancing Protein Secretion and Cytolytic Activity. PLoS Pathog 10(11): e32767. doi:10.1371/journal.ppat.1004488
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004488

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Zdroje

1. BillkerO, LindoV, PanicoM, EtienneAE, PaxtonT, et al. (1998) Identification of xanthurenic acid as the putative inducer of malaria development in the mosquito. Nature 392 : 289–292.

2. LouridoS, ShumanJ, ZhangC, ShokatKM, HuiR, et al. (2010) Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma. Nature 465 : 359–362.

3. MoudyR, ManningTJ, BeckersCJ (2001) The loss of cytoplasmic potassium upon host cell breakdown triggers egress of Toxoplasma gondii. J Biol Chem 276 : 41492–41501.

4. PerssonEK, AgnarsonAM, LambertH, HitzigerN, YagitaH, et al. (2007) Death receptor ligation or exposure to perforin trigger rapid egress of the intracellular parasite Toxoplasma gondii. J Immunol 179 : 8357–8365.

5. SilvermanJA, QiH, RiehlA, BeckersC, VN, et al. (1998) Induced activation of the Toxoplasma gondii nucleoside triphosphate hydrolase leads to depletion of host cell ATP levels and rapid exit of intracellular parasites from infected cells. J Biol Chem 273 : 12352–12359.

6. DesaiSA, KrogstadDJ, McCleskeyEW (1993) A nutrient-permeable channel on the intraerythrocytic malaria parasite. Nature 362 : 643–646.

7. SchwabJC, BeckersCJM, JoinerKA (1994) The parasitophorous vacuole membrane surrounding intracellular Toxoplasma gondii functions as a molecular sieve. Proc Natl Acad Sci USA 91 : 509–513.

8. DesaiSA, RosenbergRL (1997) Pore size of the malaria parasite's nutrient channel. Proc Natl Acad Sci U S A 94 : 2045–2049.

9. GazariniML, ThomasAP, PozzanT, GarciaCR (2003) Calcium signaling in a low calcium environment: How the intracellular malaria parasite solves the problem. J Cell Biol 161 : 103–110.

10. BouchotA, MillotJM, CharpentierS, BonhommeA, VillenaI, et al. (2001) Membrane potential changes after infection of monocytes by Toxoplasma gondii. Int J Parasitol 31 : 1114–1120.

11. JacotD, Soldati-FavreD (2012) Does protein phosphorylation govern host cell entry and egress by the Apicomplexa? Int J Med Microbiol 302 : 195–202.

12. LavineMD, ArrizabalagaG (2007) Invasion and egress by the obligate intracellular parasite Toxoplasma gondii: Potential targets for the development of new antiparasitic drugs. Curr Pharm Des 13 : 641–651.

13. BrennanAJ, ChiaJ, BrowneKA, CicconeA, EllisS, et al. (2011) Protection from endogenous perforin: Glycans and the C terminus regulate exocytic trafficking in cytotoxic lymphocytes. Immunity 34 : 879–892.

14. CarruthersVB, SibleyLD (1999) Mobilization of intracellular calcium stimulates microneme discharge in Toxoplasma gondii. Mol Microbiol 31 : 421–428.

15. LovettJL, SibleyLD (2003) Intracellular calcium stores in Toxoplasma gondii govern invasion of host cells. J Cell Sci 116 : 3009–3016.

16. WetzelDM, ChenLA, RuizFA, MorenoSN, SibleyLD (2004) Calcium-mediated protein secretion potentiates motility in Toxoplasma gondii. J Cell Sci 117 : 5739–5748.

17. KumarKA, GarciaCR, ChandranVR, Van RooijenN, ZhouY, et al. (2007) Exposure of Plasmodium sporozoites to the intracellular concentration of potassium enhances infectivity and reduces cell passage activity. Mol Biochem Parasitol 156 : 32–40.

18. EndoT, TokudaH, YagitaK, KoyamaT (1987) Effects of extracellular potassium on acid release and motility initiation in Toxoplasma gondii. J Protozool 34 : 291–295.

19. CarruthersVB, MorenoSN, SibleyLD (1999) Ethanol and acetaldehyde elevate intracellular [Ca2+] and stimulate microneme discharge in Toxoplasma gondii. Biochem J 342 : 379–386.

20. MiesenbockG, De AngelisDA, RothmanJE (1998) Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins. Nature 394 : 192–195.

21. LouridoS, TangK, SibleyLD (2012) Distinct signaling pathways control Toxoplasma egress and host-cell invasion. EMBO J 31 : 4524–4534.

22. KafsackBF, PenaJD, CoppensI, RavindranS, BoothroydJC, et al. (2009) Rapid membrane disruption by a perforin-like protein facilitates parasite exit from host cells. Science 323 : 530–533.

23. HamonMA, RibetD, StavruF, CossartP (2012) Listeriolysin O: The swiss army knife of listeria. Trends Microbiol 20 : 360–368.

24. DunstoneMA, TwetenRK (2012) Packing a punch: The mechanism of pore formation by cholesterol dependent cytolysins and membrane attack complex/perforin-like proteins. Curr Opin Struct Biol 22 : 342–349.

25. RoikoMS, CarruthersVB (2013) Functional dissection of Toxoplasma gondii perforin-like protein 1 reveals a dual domain mode of membrane binding for cytolysis and parasite egress. J Biol Chem 288 : 8712–8725.

26. SibleyLD, WeidnerE, KrahenbuhlJL (1985) Phagosome acidification blocked by intracellular Toxoplasma gondii. Nature 315 : 416–419.

27. HolpertM, LuderCG, GrossU, BohneW (2001) Bradyzoite-specific expression of a P-type ATPase in Toxoplasma gondii. Mol Biochem Parasitol 112 : 293–6.

28. CharronAJ, SibleyLD (2004) Molecular partitioning during host cell penetration by Toxoplasma gondii. Traffic 5 : 855–867.

29. SchuerchDW, Wilson-KubalekEM, TwetenRK (2005) Molecular basis of listeriolysin O pH dependence. Proc Natl Acad Sci U S A 102 : 12537–12542.

30. BavdekA, GekaraNO, PriselacD, Gutierrez AguirreI, DarjiA, et al. (2007) Sterol and pH interdependence in the binding, oligomerization, and pore formation of listeriolysin O. Biochemistry 46 : 4425–4437.

31. PraperT, BesenicarMP, IstinicH, PodlesekZ, MetkarSS, et al. (2010) Human perforin permeabilizing activity, but not binding to lipid membranes, is affected by pH. Mol Immunol 47 : 2492–2504.

32. KremerK, KaminD, RittwegerE, WilkesJ, FlammerH, et al. (2013) An overexpression screen of Toxoplasma gondii rab-GTPases reveals distinct transport routes to the micronemes. PLoS Pathog 9: e1003213.

33. RoikoMS, CarruthersVB (2013) Functional dissection of Toxoplasma gondii perforin-like protein 1 reveals a dual domain mode of membrane binding for cytolysis and parasite egress. J Biol Chem 288 : 8712–8725.

34. HuynhMH, RabenauKE, HarperJM, BeattyWL, SibleyLD, et al. (2003) Rapid invasion of host cells by Toxoplasma requires secretion of the MIC2-M2AP adhesive protein complex. EMBO J 22 : 2082–2090.