Open AccessThe innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma
Author(s) -
Kanagaraju Ponnusamy,
Maria Myrsini Tzioni,
Murshida Begum,
Mark E. Robinson,
Valentina S. Caputo,
Alexia Katsarou,
Nikolaos Trasanidis,
Xiaolin Xiao,
Ioannis V. Kostopoulos,
Deena Iskander,
Irene Roberts,
Pritesh Trivedi,
Holger W. Auner,
Kikkeri N. Naresh,
Aristeidis Chaidos,
Anastasios Karadimitris
Publication year - 2021
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2020.274480
Subject(s) - irf3 , plasma cell , irf4 , microbiology and biotechnology , biology , transcription factor , multiple myeloma , necroptosis , cancer research , programmed cell death , interferon regulatory factors , cell growth , innate immune system , immune system , immunology , apoptosis , gene , genetics
Multiple myeloma is a malignancy of plasma cells (PC) initiated and driven by primary and secondary genetic events. Nevertheless, myeloma PC survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B cell development in both human and mouse cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma PC, interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the PC lineage-defining transcription factor IRF4, and thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a non-canonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology.