Transcription of the NKG2D ligand MICA is suppressed by the IRE1/XBP1 pathway of the unfolded protein response through the regulation of E2F1

Akram Obiedat, Einat Seidel, Mohamed Mahameed, Orit Bernani, Pinchas Tsukerman, Konstantinos Voutetakis, Aristotelis Chatziioannou, Mari Mcmahon, Tony Avril, Eric Chevet, Ofer Mandelboim, Boaz Tirosh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

The unfolded protein response (UPR) is an adaptive signaling pathway activated in response to endoplasmic reticulum (ER) stress. The effectors of the UPR are potent transcription activators; however, some genes are suppressed by ER stress at the mRNA level. The mechanisms underlying UPR-mediated gene suppression are less known. Exploration of the effect of UPR on NK cells ligand expression found that the transcription of NK group 2 member D (NKG2D) ligand major histocompatibility complex class I polypeptide-related sequence A/B (MICA/B) is suppressed by the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) pathway of the UPR. Deletion of IRE1 or XBP1 was sufficient to promote mRNA and surface levels of MICA. Accordingly, NKG2D played a greater role in the killing of IRE1/XBP1 knockout target cells. Analysis of effectors downstream to XBP1s identified E2F transcription factor 1 (E2F1) as linking UPR and MICA transcription. The inverse correlation between XBP1 and E2F1 or MICA expression was corroborated in RNA-Seq analysis of 470 primary melanoma tumors. While mechanisms that connect XBP1 to E2F1 are not fully understood, we implicate a few microRNA molecules that are modulated by ER stress and possess dual suppression of E2F1 and MICA. Because of the importance of E2F1 and MICA in cancer progression and recognition, these observations could be exploited for cancer therapy by manipulating the UPR in tumor cells.—Obiedat, A., Seidel, E., Mahameed, M., Berhani, O., Tsukerman, P., Voutetakis, K., Chatziioannou, A., McMahon, M., Avril, T., Chevet, E., Mandelboim, O., Tirosh, B. Transcription of the NKG2D ligand MICA is suppressed by the IRE1/XBP1 pathway of the unfolded protein response through the regulation of E2F1. FASEB J. 33, 3481–3495 (2019). www.fasebj.org.

Original languageAmerican English
Pages (from-to)3481-3495
Number of pages15
JournalFASEB Journal
Volume33
Issue number3
DOIs
StatePublished - 1 Mar 2019

Bibliographical note

Funding Information:
This research was supported by the Ministry of Science and Technology, Israel; The Ministry of Europe and Foreign Affairs, France; and the Ministry of Higher Education, Research, and Innovation, France. Research was funded by grants from the David R. Bloom Center for Pharmacy, the Dr. Adolph and Klara Brettler Center for Research in Pharmacology, the Israeli Cancer Association, the Israel Science Foundation (Grant 696/14, to B.T.), and PHC-Maimonide 2017?2018 Grant (to B.T. and E.C.). M.M. was funded by an ARED (Allocations de Recherche Doctorale, R?gion Bretagne) international doctoral fellowship. The authors declare no conflicts of interest.

Publisher Copyright:
© FASEB

Keywords

  • ER stress
  • NK cells
  • UPR
  • immunotherapy

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