title: The autophagy sensor ITPR1 protects renal carcinoma cells from NK-mediated killing.
abstract: Clear cell renal cell carcinoma (ccRCC) is dominated by inactivating mutations in VHL (von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase), leading to constitutive activation of the hypoxia-inducible factors (HIFs) and induction of a hypoxia response transcription signature. Our study demonstrated that VHL mutation results in the acquisition of ccRCC resistance to NK-mediated lysis by a mechanism involving EPAS1/HIF-2α stabilization. More importantly we identified ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of EPAS1 and as a potent regulator of NK-mediated killing through the activation of autophagy in target cells by a signal derived from NK cells. Therefore, it is conceivable to consider EPAS1 or the autophagy sensor ITPR1 as a potential target in future therapeutic protocols that aim to improve NK cell responses in patients with RCC and other solid malignancies.
authors.affiliation: a INSERM U753 , Gustave Roussy Cancer Campus , 114, rue Edouard Vaillant, F-94805 Villejuif Cedex , France .
authors.forename: Yosra
authors.initials: Y
authors.lastname: Messai
authors.forename: Muhammad Zaeem
authors.initials: MZ
authors.lastname: Noman
authors.forename: Bassam
authors.initials: B
authors.lastname: Janji
authors.forename: Meriem
authors.initials: M
authors.lastname: Hasmim
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
keywords: ITPR1; autophagy; granzyme B; hypoxia-inducible factor-2α; natural killer; renal cell carcinoma