Myeloid cell nuclear differentiation antigen controls the pathogen-stimulated type I interferon cascade in human monocytes by transcriptional regulation of IRF7

Lili Gu,David Casserly,Katherine A Fitzgerald,Andrew G Bowie,Gareth Brady,Susan Carpenter,Adrian P Bracken,Leonie Unterholzner

doi:10.1038/s41467-021-27701-x

Abstract

Type I interferons (IFNs) are critical for anti-viral responses, and also drive autoimmunity when dysregulated. Upon viral sensing, monocytes elicit a sequential cascade of IFNβ and IFNα production involving feedback amplification, but how exactly this cascade is regulated in human cells is incompletely understood. Here we show that the PYHIN protein myeloid cell nuclear differentiation antigen (MNDA) is required for IFNα induction in monocytes. Unlike other PYHINs, this is not due to a pathogen sensing role, but rather MNDA regulated expression of IRF7, a transcription factor essential for IFNα induction. Mechanistically, MNDA is required for recruitment of STAT2 and RNA polymerase II to the IRF7 gene promoter, and in fact MNDA is itself recruited to the IRF7 promoter after type I IFN stimulation. These data implicate MNDA as a critical regulator of the type I IFN cascade in human myeloid cells and reveal a new role for human PYHINs in innate immune gene induction.

Highlights

Type I interferons (IFNs) are critical for anti-viral responses, and drive autoimmunity when dysregulated
The human monocytic cell line THP-1 displayed a similar profile of myeloid cell nuclear differentiation antigen (MNDA) protein expression to primary human monocytes in that undifferentiated cells showed higher protein expression of MNDA than cells differentiated into macrophages using phorbol-12-myristate-13-acetate (PMA), and IFNα or IFNγ had little effect on protein expression in undifferentiated cells (Fig. 1b)
We measured expression of the whole PYHIN family in THP-1s. Both mRNA (Supplementary Fig. 2a–d) and protein (Fig. 1b) expression of the four main human PYHINs was evident in THP-1 cells, absent in melanoma 2 (AIM2) was only detected after IFNγ treatment

Summary

Introduction

Type I interferons (IFNs) are critical for anti-viral responses, and drive autoimmunity when dysregulated. MNDA is required for recruitment of STAT2 and RNA polymerase II to the IRF7 gene promoter, and MNDA is itself recruited to the IRF7 promoter after type I IFN stimulation These data implicate MNDA as a critical regulator of the type I IFN cascade in human myeloid cells and reveal a new role for human PYHINs in innate immune gene induction. Cell surface and endosomal pattern recognition receptors (PRRs) especially Toll-like receptors (TLRs) can detect the presence of viral and mislocalised nucleic acid, and via the signalling proteins MyD88 and Toll-interleukin-1 (IL-1) receptor domaincontaining adaptor inducing IFNβ (TRIF) activate the TANK binding kinase-1-IFN regulatory factor 3 (TBK1-IRF3) signalling axis, that causes rapid IFNβ gene induction[5]. Since IFNα signals via the IFNAR this leads to a positive feedback loop that magnifies the type I IFN response by amplifying IRF7 and IFNα induction

Methods

Results

Conclusion