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Leishmania donovani induced Unfolded Protein Response delays host cell apoptosis in PERK dependent manner.
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- Author(s): Abhishek K;Abhishek K; Das S; Das S; Kumar A; Kumar A; Kumar A; Kumar A; Kumar V; Kumar V; Saini S; Saini S; Mandal A; Mandal A; Verma S; Verma S; Kumar M; Kumar M; Das P; Das P
- Source:
PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2018 Jul 23; Vol. 12 (7), pp. e0006646. Date of Electronic Publication: 2018 Jul 23 (Print Publication: 2018).- Publication Type:
Journal Article; Research Support, Non-U.S. Gov't- Language:
English - Source:
- Additional Information
- Source: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101291488 Publication Model: eCollection Cited Medium: Internet ISSN: 1935-2735 (Electronic) Linking ISSN: 19352727 NLM ISO Abbreviation: PLoS Negl Trop Dis Subsets: MEDLINE
- Publication Information: Original Publication: San Francisco, CA : Public Library of Science
- Subject Terms: Apoptosis* ; Unfolded Protein Response*; Leishmania donovani/*physiology ; Leishmaniasis, Visceral/*enzymology ; Leishmaniasis, Visceral/*physiopathology ; Macrophages/*parasitology ; eIF-2 Kinase/*metabolism; Animals ; Endoplasmic Reticulum Stress ; Host-Parasite Interactions ; Humans ; Inhibitor of Apoptosis Proteins/genetics ; Inhibitor of Apoptosis Proteins/metabolism ; Leishmania donovani/genetics ; Leishmaniasis, Visceral/parasitology ; Macrophages/enzymology ; Mice ; Phosphorylation ; RAW 264.7 Cells ; eIF-2 Kinase/genetics
- Abstract: Background: Endoplasmic reticulum (ER) stress generated unfolded stress response (UPR) is a basic survival mechanism which protects cell under unfavourable conditions. Leishmania parasite modulates host macrophages in various ways to ensure its survival. Modulation of PI3K-Akt pathway in delayed apoptotic induction of host; enables parasite to stabilize the infection for further propagation.
Methodology: Infected RAW macrophages were exposed to campothecin or thagsigargin and phosphorylation status of PERK, Akt, BAD and Cyt-C was determined through western blotting using phospho specific antibody. Expression at transcriptional level for cIAP1 &2, ATF4, CHOP, ATF3, HO-1 and sXBP1 was determined using real time PCR. For inhibition studies, RAW macrophages were pre-treated with PERK inhibitor GSK2606414 before infection.
Findings: Our studies in RAW macrophages showed that induction of host UPR against L.donovani infection activates Akt mediated pathway which delays apoptotic induction of the host. Moreover, Leishmania infection results in phosphorylation and activation of host PERK enzyme and increased transcription of genes of inhibitor of apoptosis gene family (cIAP) mRNA. In our inhibition studies, we found that inhibition of infection induced PERK phosphorylation under apoptotic inducers reduces the Akt phosphorylation and fails to activate further downstream molecules involved in protection against apoptosis. Also, inhibition of PERK phosphorylation under oxidative exposure leads to increased Nitric Oxide production. Simultaneously, decreased transcription of cIAP mRNA upon PERK phosphorylation fates the host cell towards apoptosis hence decreased infection rate.
Conclusion: Overall the findings from the study suggests that Leishmania modulated host UPR and PERK phosphorylation delays apoptotic induction in host macrophage, hence supports parasite invasion at early stages of infection.
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EC 2.7.11.1 (PERK kinase)
EC 2.7.11.1 (eIF-2 Kinase) - Publication Date: Date Created: 20180724 Date Completed: 20181127 Latest Revision: 20181127
- Publication Date: 20240105
- Accession Number: PMC6081962
- Accession Number: 10.1371/journal.pntd.0006646
- Accession Number: 30036391
- Source:
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