当前位置： SCI文献检索 > CYTOKINE期刊下所有文献 > Protein translocation and retro-translocation across the endoplasmic reticulum are crucial to inflammatory effector CD4+ T cell function.

Protein translocation and retro-translocation across the endoplasmic reticulum are crucial to inflammatory effector CD4+ T cell function.

Abstract：

:Effector CD4+ T cells can be classified by the cytokines they secrete, with T helper 1 (Th1) cells generating interferon (IFN)γ and Th17 cells secreting interleukin (IL)-17. Both Th1 and Th17 cells are strongly implicated in the initiation and chronicity of autoimmune diseases such as multiple sclerosis. The endoplasmic reticulum (ER) has been implicated as a potentially crucial site in regulating CD4+ T cell function. Secretory and transmembrane proteins are shuttled into the ER via the Sec61 translocon, where they undergo appropriate folding; misfolded proteins are retro-translocated from the ER in a p97-dependent manner. Here, we provide evidence that both processes are crucial to the secretion of inflammatory cytokines from effector CD4+ T cells. The pan-ER inhibitor eeeyarestatin-1 (ESI), which interferes with both Sec61 translocation and p97 retro-translocation, inhibited secretion of interferon (IFN)γ, interleukin (IL)-2 and tumor necrosis factor (TNF)α from Th1 cells in a dose-dependent manner. Selective inhibition of Sec61 by Apratoxin A (ApraA) revealed that ER translocation is crucial for Th1 cytokine secretion, while inhibition of p97 by NMS-873 also inhibited Th1 function, albeit to a lesser degree. By contrast, none of ESI, ApraA or NMS-873 could significantly reduce IL-17 secretion from Th17 cells. ApraA, but not NMS-873, reduced phosphorylation of Stat1 in Th1 cells, indicating the involvement of ER translocation in Th1 differentiation pathways. ApraA had modest effects on activation of the Th17 transcription factor Stat3, while NMS-873 had no effect. Interestingly, NMS-873 was able to reduce disease severity in CD4+ T cell-driven experimental autoimmune encephalomyelitis (EAE). Together, our data indicate that CD4+ T cell function, and Th1 cell function in particular, is dependent on protein translocation and dislocation across the ER.

journal_name

Cytokine

journal_title

Cytokine

authors

Pradeep Yeola A,Akbar I,Baillargeon J,Mercy Ignatius Arokia Doss P,Paavilainen VO,Rangachari M

doi

10.1016/j.cyto.2019.154944

subject

Has Abstract

pub_date

2020-05-01 00:00:00

pages

154944

eissn

1043-4666

issn

1096-0023

pii

S1043-4666(19)30373-4

journal_volume

129

pub_type

杂志文章

在线工具

Protein translocation and retro-translocation across the endoplasmic reticulum are crucial to inflammatory effector CD4+ T cell function.