Glucocorticoid-induced leucine zipper (GILZ)/NF- B interaction: role of GILZ homo-dimerization and C-terminal domain

Abstract

Glucocorticoid-induced leucine zipper (GILZ) is a 137 amino acid protein, rapidly induced by treatment with glucocorticoids (GC), characterized by a leucine zipper (LZ) domain (76–97 amino acids), an N-terminal domain (1–75 amino acids) and a C-terminal PER domain (98–137 amino acids) rich in proline and glutamic acid residues. We have previously shown that GILZ binds to and inhibits NF-κB activity. In the present study we used a number of mutants with the aim of defining the GILZ molecular domains responsible for GILZ/p65NF-κB interaction. Results, obtained by in vitro and in vivo co-immunoprecipitation (Co-IP) and by transcriptional activity experiments, indicate that GILZ homo-dimerization, through the LZ domain, as well as the C-terminal PER domain, particularly the 121–123 amino acids, are both necessary for GILZ interaction with NF-κB, inhibition of transcriptional activity and of IL-2 synthesis.

Glucocorticoid-Induced Leucine Zipper (GILZ) Over-Expression in T Lymphocytes Inhibits Inflammation and Tissue Damage in Spinal Cord Injury

“…These results are in accordance with observations suggesting GILZ can inhibit T-lymphocyte activation, cytokine production, and the inflammatory processes in vitro and in vivo [15-18, 20, 24, 37, 38]. Moreover, results described herein are also in accordance with the GILZ capability to counter NF-κB activation [16,17,21,39], and in fact a significant inhibition of SCI-induced NF-κB activation and nuclear translocation is evident in GILZ TG mice. Notably, this NF-κB inhibition may well explain the lower inflammation that develops in GILZ TG , in comparison to WT mice, after SCI induction.…”

“…The GILZ gene encodes various isoforms among which GILZ is the isoform expressed in normal T lymphocytes that mediates some of the immunomodulatory effects of GC, including inhibition of NF-κB activation and nuclear translocation [15][16][17][18][19][20][21]. Notably, GILZ directly interacts with NF-κB in a homodimeric conformation through specific amino acids at the COOH terminal domain [21]. Moreover, GILZ can interact with Ras-dependent mitogen activated protein kinase pathway, in a monomeric conformation and through its NH2 terminal domain, with consequent inhibition of the downstream pathways, including NF-κB activation [22].…”

“…Moreover, GILZ can interact with Ras-dependent mitogen activated protein kinase pathway, in a monomeric conformation and through its NH2 terminal domain, with consequent inhibition of the downstream pathways, including NF-κB activation [22]. Thus, GILZ inhibits NF-κB by multiple mechanisms and acts as an anti-inflammatory molecule [15,[20][21][22][23][24].…”

Anti-inflammatory functions of glucocorticoid-induced genes

“…GILZ is a 137 amino acid protein with a central leucine zipper (LZ) dimerization domain. Unlike other LZ proteins it is not known to bind directly to DNA, but interacts with NFκB and impairs its transactivation function Berrebi et al, 2003;DiMarco et al, 2006;Eddleston et al, 2007;Riccardi et al, A c c e p t e d M a n u s c r i p t…”

Role of the glucocorticoid‐induced leucine zipper gene in dexamethasone‐induced inhibition of mouse neutrophil migration via control of annexin A1 expression

“…GILZ mainly exerts its effects by homo-or heterodimerization with specific partner proteins, including transcription factors, such as NF-kB, and Ras/Raf. The homo-and heterodimers formed then regulate expression of target genes at the transcription level (10)(11)(12)(13).…”