A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity

Abstract

Interferon-α (IFN-α) is essential for antiviral immunity, but in the absence of matrix metalloproteinase-12 (MMP-12) or IκBα (encoded by NFKBIA) we show that IFN-α is retained in the cytosol of virus-infected cells and is not secreted. Our findings suggest that activated IκBα mediates the export of IFN-α from virus-infected cells and that the inability of cells in Mmp12(-/-) but not wild-type mice to express IκBα and thus export IFN-α makes coxsackievirus type B3 infection lethal and renders respiratory syncytial virus more pathogenic. We show here that after macrophage secretion, MMP-12 is transported into virus-infected cells. In HeLa cells MMP-12 is also translocated to the nucleus, where it binds to the NFKBIA promoter, driving transcription. We also identified dual-regulated substrates that are repressed both by MMP-12 binding to the substrate's gene exons and by MMP-12-mediated cleavage of the substrate protein itself. Whereas intracellular MMP-12 mediates NFKBIA transcription, leading to IFN-α secretion and host protection, extracellular MMP-12 cleaves off the IFN-α receptor 2 binding site of systemic IFN-α, preventing an unchecked immune response. Consistent with an unexpected role for MMP-12 in clearing systemic IFN-α, treatment of coxsackievirus type B3-infected wild-type mice with a membrane-impermeable MMP-12 inhibitor elevates systemic IFN-α levels and reduces viral replication in pancreas while sparing intracellular MMP-12. These findings suggest that inhibiting extracellular MMP-12 could be a new avenue for the development of antiviral treatments.

Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

“…MMP-12 contributes to cell migration (33) of DC and leukocytes (31,34). The ability of MMP-12 to cleave off IFN-α receptor 2-binding sites (35) blocks the action of type I IFN, which in previous work we showed blocks antimicrobial responses in leprosy (16). The presence of MMP-12 in T-lep and RR granulomas, as well as other granulomatous diseases such as sarcoidosis (36), suggests that MMP-12 is part of a tissue remodeling and inflammation gene network that contributes to granuloma formation and/or maintenance.…”

Multiple myeloma–derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease

“…Efforts are currently underway to identify the MMP-13 receptor(s) that are operative in OCL progenitors, with preliminary cross-linking and mass spectroscopic studies having identified a number of potential cell-surface ligands whose expression will require silencing on a one-by-one basis (our unpublished observation). These studies will, by necessity, need to proceed cautiously, as several MMPs including MMP-13 can regulate diverse cell functions by trafficking to the nuclear compartment to exert transcriptional effects (61,62).…”

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

“…70 Further examples are nonenzymatic functions of matrix metalloproteinase 12 and the g-secretase component presenilin 1. 71,72 BACE1 itself has been discussed as a non-enzymatic binding partner for a set of proteins, including BRI3, which is, like BACE1, processed by furin. 73 While in Na v channels, non-enzymatic interactions between BACE1 and channel proteins were clearly discernible but small, such effects became much more prominent when explored in members of the KCNQ family.…”