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Rac1 and Cdc42 are involved in the periphagosomal F-actin accumulation and inhibition of phagosomal maturation caused by Leishmania donovani lipophosphoglycan
Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
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(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Abstract [en]

The intracellular parasite Leishmania donovani survives inside macrophage phagosomes by inhibiting phagosornal maturation. Its main surface glycoconjugate, lipophosphoglycan (LPG), is crucial for survival and essential for the build-up of a coat of F-actin surrounding the phagosome. Previous studies have shown that inhibition of PKCα by LPG is partly responsible for the elevated levels of F-actin around the phagosome (1, 2). This study shows that simultaneous inhibition of Cdc42 and Rac1, members of the Rho family of small GTPases, prevented the accumulation of F-actin around L. donovani containing phagosomes in murine macrophages. Moreover, an LPG-defective L. donovani mutant normally not capable of accumulating F-actin around it's phagosome, displayed elevated amounts of periphagosomal F-actin in cells pre-treated with permanently active forms of Cdc42 and Rac. The lysosomal marker LAMP1 did not translocate normally to phagosomes in these cells, indicating defective phagosomal maturation. We conclude that Cdc42 and Rac are activated by L. donovani in an LPG-dependent manner, and that this activation contributes to the accumulation of periphagosomal F-actin around L. donovani phagosomes. Our results also indicate a direct link between the build-up of periphagosomal F-actinand inhibition of phagosomal mahuation.

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Identifikatorer
URN: urn:nbn:se:liu:diva-84526OAI: oai:DiVA.org:liu-84526DiVA, id: diva2:560069
Tilgjengelig fra: 2012-10-11 Laget: 2012-10-11 Sist oppdatert: 2012-10-11bibliografisk kontrollert
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1. Leishmania donovani lipophosphoglycan: effects on actin and phagosomal maturation
Åpne denne publikasjonen i ny fane eller vindu >>Leishmania donovani lipophosphoglycan: effects on actin and phagosomal maturation
2003 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Leishmania donovani promastigotes survive intracellularly in macrophages by inhibiting phagosomal maturation. This ability is conferred by surface lipophosphoglycan (LPG), which is transferred to the host-cell plasma and phagosomal membranes during phagocytosis. LPG modulates the biophysical properties of membranes and has several effects on the host cell, including inhibition of protein kinase C alpha (PKCα)-mediated signaling. Our studies were focused on molecular mechanisms operating in the establishment of L. donovani infection, especially effects on host-cell F-actin.

We found that L. donovani promastigotes induced accumulation of periphagosomal F-actin, an effect directly dependent on LPG. The F-actin accumulation correlated to inhibition of phagosomal maturation. Cortical F-actin was increased as well. Macrophages overexpressing dominant-negative (DN) PKCα also displayed elevated cortical F-actin, decreased phagocytic capacity, elevated periphagosomal F-actin, and defective phagosomal maturation, effects similar to those seen when exposing the cells to LPG. LPG colocalized with lipid rafts in the host-cell membrane, and lipid rafts were necessary both for translocation of activated PKCα to the membrane, and for the effects of LPG on host cell actin dynamics and phagosomal maturation. Introduction of constitutively active Rac1 and Cdc42 into the host macrophage mimicked the effects of LPG on actin dynamics and phagosomal maturation while DN Rac1 and Cdc42 abrogated LPG's effects on actin.

Taken together, our results show that LPG partitions into lipid rafts in macrophages and induces an accumulation of periphagosomal F-actin, which is correlated to inhibition of phagosomal maturation. The effect of LPG on actin involves inhibition of PKCα and depends on active Rac1 and Cdc42.

sted, utgiver, år, opplag, sider
Linköping: Linköpings universitet, 2003. s. 106
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 800
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-26655 (URN)11220 (Lokal ID)91-7373-489-6 (ISBN)11220 (Arkivnummer)11220 (OAI)
Disputas
2003-09-18, Aulan, Hälsans Hus, Hälsouniversitet, Linköping, 09:00 (svensk)
Opponent
Tilgjengelig fra: 2009-10-08 Laget: 2009-10-08 Sist oppdatert: 2012-10-11bibliografisk kontrollert

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