MTA1 Coregulation of Transglutaminase 2 Expression and Function during Inflammatory Response

Abstract

Although both metastatic tumor antigen 1 (MTA1), a master chromatin modifier, and transglutaminase 2 (TG2), a multifunctional enzyme, are known to be activated during inflammation, it remains unknown whether these molecules regulate inflammatory response in a coordinated manner. Here we investigated the role of MTA1 in the regulation of TG2 expression in bacterial lipopolysaccharide (LPS)-stimulated mammalian cells. While studying the impact of MTA1 status on global gene expression, we unexpectedly discovered that MTA1 depletion impairs the basal as well as the LPS-induced expression of TG2 in multiple experimental systems. We found that TG2 is a chromatin target of MTA1 and of NF-B signaling in LPSstimulated cells. In addition, LPS-mediated stimulation of TG2 expression is accompanied by the enhanced recruitment of MTA1, p65RelA, and RNA polymerase II to the NF-B consensus sites in the TG2 promoter. Interestingly, both the recruitment of p65 and TG2 expression are effectively blocked by a pharmacological inhibitor of the NF-B pathway. These findings reveal an obligatory coregulatory role of MTA1 in the regulation of TG2 expression and of the MTA1-TG2 pathway, at least in part, in LPS modulation of the NF-B signaling in stimulated macrophages.Inflammation is an adaptive immune response triggered by the body against detrimental stimuli and conditions such as microbial infection and tissue injury (1, 2). Inflammation is usually a healing response, but it becomes detrimental if targeted destruction and assisted repair are not properly activated (3). Primarily, macrophages and mast cells recognize the infection and produce a wide variety of inflammatory mediators such as chemokines, cytokines, etc., all contributing to the elicitation of an inflammatory response (1). The inflammatory response is characterized by coordinated regulation of signaling pathways that regulate the expression of both the pro-inflammatory and the anti-inflammatory cytokines including IL-1, IL-6, TNF-␣, receptor activator of NF-B ligand (RANKL), etc. (4). The inability of host to regulate inflammatory response results in sepsis, organ dysfunction, and even death (5). These inflammatory cytokines are under the tight control of master gene transcriptional factor NF-B in promoting the inflammation, and in turn, innate immunity (6). Furthermore, transcriptional control of such NF-B genomic targets is also under a tight control of nucleosome-remodeling coregulators and complexes, leading to either the stimulation or the repression of gene transcription at the molecular level (7-10).In recent times, metastatic tumor antigen 1 (MTA1) 3 has been recognized as one of the major coregulators in mammalian cells. MTA1 is a ubiquitously expressed chromatin modifier, having an integral role in nucleosome-remodeling and histone deacetylase (NuRD) complexes (11). MTA1 is widely up-regulated in a wide variety of human tumors and has been shown to play a role in tumorigenesis (11-14). MTA1 regulates transcription of its targets by modifying the acetylation stat...

Subcellular localization of MTA proteins in normal and cancer cells

“…MTA1 plays an essential role in DNA damage response [35][36][37][38], a process that is important for both normal and cancer cells. Recent advances have also revealed that MTA1 plays a critical homeostatic role in inflammatory responses, both as a target and as a component of the NF-κB circuitry [39][40][41], which links normal and cancer cells. The association of MTA1 with microtubules [19] may endow MTA1 with basic physiological roles in the regulation of cell shape, cell motility, and cell cycle, among other factors.…”

“…However, the static and co-repressive complex cannot explain the co-activator function of MTA1. MTA1 has been reported to co-activate the transcription of many genes, such as BCAS3 [96], Pax5 [72], MyD88 [40], p19ARF [97], transglutaminase 2 (TG2) [41], HMMR [98], tyrosine hydroxylase (TH) [99], SUMO2 [100], and STAT3 [101]. All of these activities involve MTA1-RNA pol II co-activator complex recruitment.…”

MTA1 expression correlates significantly with cigarette smoke in non-small cell lung cancer

“…As a part of the NuRD complex, MTA1 regulates transcription of its targets by modifying the acetylation status of the target chromatin and cofactor accessibility to the target DNA [2]. Current models suggest that MTA1 regulates metastatic potential as part of the multiprotein Mi-2/nucleosome remodeling and NuRD by controlling the epithelial-tomesenchymal transition [3,4].…”

Physiological functions of MTA family of proteins

“…Unexpectedly, MTA1 manifests its dual coregulatory activity in the inflammatory response: under basal condition, MTA1 represses the expression of target cytokine genes while acting as an coactivator of cytokines in LPS-stimulated macrophages [41]. Additionally, LPS stimulation of macrophage is accompanied by increased expression of cytokines [42]; MTA1 also stimulates the expression of transglutaminase 2 - a crosslinking enzyme involved in immediate defense during injury or infection in LPS-stimulated cells [43]. These observations raise an interesting possibility that MTA1 expression is likely to be induced by extracellular signals which themselves induce NF-κB signaling pathway.…”