␣-Actinin is tyrosine-phosphorylated in activated human platelets (Izaguirre, G., Aguirre, L., Ji, P., Aneskievich, B., and Haimovich, B. (1999) J. Biol. Chem. 274, 37012-37020). Analysis of platelet RNA by reverse transcription-polymerase chain reaction revealed that ␣-actinin expressed in platelets is identical to the cytoskeletal/non-muscle isoform. A construct of this isoform containing a His 6 tag at the amino terminus was generated. Robust tyrosine phosphorylation of the recombinant protein was detected in cells treated with the tyrosine phosphatase inhibitor vanadate. The tyrosine phosphorylation site was localized to the amino-terminal domain by proteolytic digestion. A recombinant ␣-actinin protein containing a Tyr 3 Phe mutation at position 12 (Y12F) was no longer phosphorylated when expressed in vanadate-treated cells, indicating that tyrosine 12 is the site of phosphorylation. The wild type recombinant protein was not phosphorylated in cells lacking the focal adhesion kinase (FAK). Re-expression of FAK in these cells restored ␣-actinin phosphorylation. Purified wild type ␣-actinin, but not the Y12F mutant, was phosphorylated in vitro by wild type as well as a Phe-397 mutant of FAK. In contrast, no phosphorylation was detected in the presence of a kinase-dead FAK. Tyrosine phosphorylation reduced the amount of ␣-actinin that cosedimented with actin filaments. These results establish that ␣-actinin is a direct substrate for FAK and suggest that ␣-actinin mediates FAK-dependent signals that could impact the physical properties of the cytoskeleton.

Nuclear receptor (NR) transcriptional activity is controlled by agonist binding and concomitant exchange of receptor-associating corepressor proteins for NR box-containing, receptor AF-2-targeting coactivator proteins. We report here that TNIP1 is an atypical NR coregulator. Requirements for TNIP1-RAR interaction -its NR boxes, ligand, and the receptor's AF-2 domainare characteristic of coactivators. However, TNIP1 reduces RAR activity. Repression is partially relieved by SRC1, suggesting interference with coactivator recruitment as a mechanism of TNIP1 repression. TNIP1 does not bind RXRα and RARα AF-2 domain, necessary for that receptor's association with TNIP1, is insufficient to confer upon RXRα interaction with TNIP1. Preferential interaction of RARα over RARγ with TNIP1 can be mapped to RARα ligand binding domain helices 5-9 and suggests regions outside the receptor helix 12 modulate interaction of NRs and NR box containing corepressors. TNIP1 repression of RARs in the presence of RA places it in a small category of corepressors of agonist-bound NRs.

Nuclear receptors (NRs) rely on coregulator proteins to modulate transcription of target genes. NR coregulators can be broadly subdivided into coactivators which potentiate transcription and corepressors which silence gene expression. The prevailing view of coregulator action holds that in the absence of agonist the receptor interacts with a corepressor via the corepressor nuclear receptor (CoRNR, "corner") box motifs within the corepressor. Upon agonist binding, a conformational change in the receptor causes the shedding of corepressor and the binding of a coactivator which interacts with the receptor via NR boxes within the coregulator. This view was challenged with the discovery of RIP140 which acts as a NR corepressor in the presence of agonist and utilizes NR boxes. Since then a number of other corepressors of agonist-bound NRs have been discovered. Among them are LCoR, PRAME, REA, MTA1, NSD1, and COPR1 Although they exhibit a great diversity of structure, mechanism of repression and pathophysiological function, these corepressors frequently have one or more NR boxes and often recruit histone deacetylases to exert their repressive effects. This review highlights these more recently discovered corepressors and addresses their potential functions in transcription regulation, disease pharmacologic responses and xenobiotic metabolism.

TNIP1 protein is increasingly being recognized as a key repressor of inflammatory signaling and a potential factor in multiple autoimmune diseases. In addition to earlier foundational reports of TNIP1 SNPs in human autoimmune diseases and TNIP1 protein-protein interaction with receptor regulating proteins, more recent studies have identified new potential interaction partners and signaling pathways likely modulated by TNIP1. Subdomains within the TNIP1 protein as well as how they interact with ubiquitin have not only been mapped but inflammatory cell- and tissue-specific consequences subsequent to their defective function are being recognized and related to human disease states such as lupus, scleroderma, and psoriasis. In this review, we emphasize receptor signaling complexes and regulation of cytoplasmic signaling steps downstream of TLR given their association with some of the same autoimmune diseases where TNIP1 has been implicated. TNIP1 dysfunction or deficiency may predispose healthy cells to the inflammatory response to otherwise innocuous TLR ligand exposure. The recognition of the anti-inflammatory roles of TNIP1 and improved integrated understanding of its physical and functional association with other signaling pathway proteins may position TNIP1 as a candidate target for the design and/or testing of next-generation anti-inflammatory therapeutics.

A vast number of cellular processes and signaling pathways are regulated by various receptors, ranging from transmembrane to nuclear receptors. These receptor-mediated processes are modulated by a diverse set of regulatory proteins. TNFα-induced protein 3-interacting protein 1 is such a protein that inhibits both transduction by transmembrane receptors, such as TNFα-receptor, EGF-R, and TLR, and nuclear receptors’ PPAR and RAR activity. These receptors play key roles in regulating inflammation and inflammatory diseases. A growing number of references have implicated TNIP1 through GWAS and expression studies in chronic inflammatory diseases such as psoriasis and rheumatoid arthritis, although TNIP1’s exact role has yet been determined. In this review, we aim to integrate the current knowledge of TNIP1’s functions with the diseases in which it has been associated to potentially elucidate the role this regulator has in promoting or alleviating these inflammatory diseases.