The JNK/AP-1 pathway upregulates expression of the recycling endosome rab11a gene in B cells transformed by Theileria

Abstract

SummaryLymphocyte transformation induced by Theileria parasites involves constitutive activation of c-Jun N-terminal kinase (JNK) and the AP-1 transcription factor. We found that JNK/AP-1 activation is associated with elevated levels of Rab11 protein in Theileriatransformed B cells. We show that AP-1 regulates rab11a promoter activity in B cells and that the induction of c-Jun activity in mouse fibroblasts also leads to increased transcription of the endogenous rab11a gene, consistent with it being an AP-1 target. Pharmacological inhibition of the JNK pathway reduced Rab11 protein levels and endosome recycling of transferrin receptor (TfR) and siRNA knockdown of JNK1 and Rab11A levels also reduced TfR surface expression. We propose a model, where activation of the JNK/AP-1 pathway during cell transformation might assure that the regulation of recycling endosomes is co-ordinated with cell-cycle progression. This might be achieved via the simultaneous upregulation of the cell cycle machinery (e.g. cyclin D1) and the recycling endosome regulators (e.g. Rab11A).

Desmoglein 3 regulates membrane trafficking of cadherins, an implication in cell-cell adhesion

“…We have reported recently that Dsg3 is capable of regulating the transcription factor c-Jun/AP-1 11 and the evidence for JNK/AP-1 in regulating the Rab gene expression has been documented in Theileria-transformed B cells. 35 Thus, it is possible that our observed change in the Rab protein expression was caused by JNK/AP-1 activation induced by Dsg3 and loss of Dsg3 function could consequently cause a reduction in the Rab expression and therefore the defects in cadherin trafficking, as we showed here in cells with Dsg3 knockdown or with its mutant expression. Rab proteins are small GTPases that cycle between GTP-and GDP bound status and serve as the scaffolds to integrate both the membrane trafficking and intracellular signaling in a temporally and spatially sensitive manner.…”

Hijacking of Host Cell Signaling by Theileria

“…In a further study, a potential AP1 binding site was identified in the Rab11a promoter (REF 43). JNK also regulates AP1 activity [28,30], and pharmacological inhibition of the JNK pathway reduced Rab11 protein levels and endosome recycling of the TfR; furthermore, siRNA knockdown of JNK1 levels reduced TfR surface expression [43]. Whether PI3K and JNK function in the same signaling pathway was not directly determined, however.…”

Theileria highjacks JNK2 into a complex with the macroschizont GPI (GlycosylPhosphatidylInositol)-anchored surface protein p104

“…Known as the only eukaryote pathogen to transform a eukaryote host cell, Theileria achieves this by manipulating host cell signalling pathways, reviewed in B. Shiels et al (). Several different signalling pathways have been implicated, including TGF‐β (Chaussepied et al, ; Haidar et al, ; Haidar, Echebli, Ding, Kamau, & Langsley, ) and JNK kinase leading to constitutive phosphorylation of c‐Jun and activation of AP‐1 (Adamson, Logan, Kinnaird, Langsley, & Hall, ; Baylis et al, ; Chaussepied et al, ; Lizundia et al, ).…”

“…Theileria ‐dependent JNK1 activity is required for survival of T. parva transformed B lymphocytes, as demonstrated by overexpression of a dominant negative kinase‐dead mutant of JNK1 and/or via the use of pan‐JNK inhibitor (pan‐JNKi; Lizundia et al, , ). Whereas the parasite‐derived molecular mechanism(s) underlying JNK activation is unknown, JNK1‐mediated survival of Theileria‐ transformed leukocytes has been attributed to AP‐1‐driven expression of the anti‐apoptotic genes Mcl‐1 and c‐IAP (Lizundia et al, ), and uncontrolled proliferation is linked to AP‐1‐driven expression of transferrin receptor and cyclin D1 (Lizundia et al, ).…”