Role of PKCδ in IFN-γ-inducible CIITA gene expression☆

Kwon, Myung Ja; Yao, Yongxue; Walter, Michael; Holtzman, Michael J.; Chang, Cheong Hee

doi:10.1016/j.molimm.2007.01.035

Cited by 16 publications

(21 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because Rho family GTPases are involved in a variety of immune responses as well as cellular functions, statin-mediated inhibition of Rho family GTPases' function provides a better understanding of the molecular mechanisms and diverse actions of statins. Other signaling pathways such as activation of PKCδ, PKCα and PKCβII have been implicated in CIITA gene expression [41, 42]. It will be of interest to determine if statins influence these signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

The IFN‐γ‐induced transcriptional program of the CIITA gene is inhibited by statins

2008

View full text Add to dashboard Cite

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors that exert anti-inflammatory effects. IFN-c induction of class II MHC expression, which requires the class II transactivator (CIITA), is inhibited by statins; however, the molecular basis for suppression is undetermined. We describe that statins inhibit IFN-c-induced class II MHC expression by suppressing CIITA gene expression, which is dependent on the HMG-CoA reductase pathway. In addition, CIITA expression is inhibited by GGTI-298 or Clostridium difficile Toxin A, specific inhibitors of Rho family protein prenylation, indicating the involvement of small GTPases. Rac1 is involved in IFN-c inducible expression of CIITA, and statins inhibit IFN-c-induced Rac1 activation, contributing to the inhibitory effect of statins. IFN-c induction of the CIITA gene is regulated by the transcription factors STAT-1a, interferon regulatory factor (IRF)-1 and upstream stimulatory factor (USF)-1. We previously reported that statins inhibit constitutive STAT-1a expression. IRF-1, a STAT-1 dependent gene, is also inhibited by statins. Therefore, statin treatment results in decreased recruitment of STAT-1a and IRF-1 to the endogenous CIITA promoter IV (pIV). The recruitment of USF-1 to CIITA pIV is also reduced by statins, as is the recruitment of RNA polymerase II (Pol II), p300 and Brg-1. These data indicate that statins inhibit the transcriptional program of the CIITA gene.

show abstract

Section: Discussionmentioning

confidence: 99%

The IFN‐γ‐induced transcriptional program of the CIITA gene is inhibited by statins

2008

View full text Add to dashboard Cite

show abstract

“…More recent evidence has shown that the activity of CIITA is tightly regulated at multiple levels, including expression, GTP binding, dimerization, nuclear translocation, and phosphorylation (42,(61)(62)(63)(64)(65), whereas the intracellular signaling pathways involved in CIITA regulation, namely phosphorylation, are only starting to emerge. Although several kinases have been identified as mediators of CIITA expression and function, their respective roles differ, reflecting a complex regulatory mechanism alternatively capable of activating or inhibiting CIITA function.…”

Section: Discussionmentioning

confidence: 99%

Mitogen-activated Protein Kinase ERK1/2 Regulates the Class II Transactivator

Voong

Slater

Kratovac

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

The expression of major histocompatibility class II genes is necessary for proper antigen presentation and induction of an immune response. This expression is initiated by the class II transactivator, CIITA. The establishment of the active form of CIITA is controlled by a series of post-translational events, including GTP binding, ubiquitination, and dimerization. However, the role of phosphorylation is less clearly defined as are the consequences of phosphorylation on CIITA activity and the identity of the kinases involved. In this study we show that the extracellular signal-regulated kinases 1 and 2 (ERK1/2) interact directly with CIITA, targeting serine residues in the amino terminus of the protein, including serine 288. Inhibition of this phosphorylation by dominant-negative forms of ERK or by treatment of cells with the ERK inhibitor PD98059 resulted in the increase in CIITA-mediated gene expression from a class II promoter, enhanced the nuclear concentration of CIITA, and impaired its ability to bind to the nuclear export factor, CRM1. In contrast, inhibition of ERK1/2 activity had little effect on serine-to-alanine mutant forms of CIITA. These data suggest a model whereby ERK1/2-mediated phosphorylation of CIITA down-regulates CIITA activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.The class II transactivator CIITA 2 plays a critical role in initiating an immune response by activating the expression of major histocompatibility (MHC) class II genes and associated molecules (2-6). MHC II glycoproteins are necessary for the presentation of antigenic peptides to CD4 ϩ T lymphocytes and the subsequent initiation and propagation of CD4 ϩ T cell-mediated immune responses and are involved in the development and maintenance of homeostasis of the CD4 ϩ T cell population. Although constitutive expression of MHC class II genes is primarily restricted to a specific subset of antigen-presenting cells that include B cells and dendritic cells, expression is inducible in a variety of other cell types and tissues by cytokines such as interferon-␥ and tumor necrosis factor-␣ (1). Both constitutive and inducible expression of MHC II and other related genes are contingent upon the activation of CIITA (7,8). Loss of a functional CIITA protein results in an immunodeficiency called bare lymphocyte syndrome, which is characterized by a complete absence of MHC class II-mediated antigen presentation. Patients with this disease suffer from recurrent infections due to opportunistic infections and, ultimately, death in early childhood (9 -11).CIITA is a protein of 1130 amino acids that does not bind directly to DNA. Instead, it regulates gene expression by interacting with other transcription factors and chromatin-remodeling proteins at the W/X/Y regulatory elements in the promoter regions of class II genes (for review, see Refs. 12-17). Nuclear factors binding to CIITA include the regulatory factor X (RFX) complex (RFX5, RFXAP, RFXANK/RFX-B) (18) and nuc...

show abstract

“…In the Type II IFN system five different serine kinases for the transactivation domain (TAD) of Stat1/phosphorylation on serine 727 have been demonstrated in different cell systems. These include PKCδ (30, 31), calmodulin dependent kinase II (CAMKII) (32), PKCε (33), PKCα (34), Erk (35) and cyclin dependent kinase 8 (CDK8) (36) (Table 2). Thus, it appears that in the Type I IFN system, PKCδ is the predominant kinase that regulates phosphorylation of Stat1 on serine 727 (Table 2), while in the Type II IFN system several serine kinases appear to play roles in different cell types (Table 2).…”

Section: Jak-stat Pathwaysmentioning

confidence: 99%

“…SOCS1 targeting by miR-122 in liver Huh7 cells significantly increases type I IFN expression (109). miR-29 targets IFNγ mRNA and the transcription factors T-bet and Eomes, inhibiting IFNγ production (130, 31). Additionally, using miR databases, at least 17 miRs have been identified that potentially target IFNγ, including miR-29 (132).…”

Section: Micrornas (Mirs) and The Ifn Responsementioning

confidence: 99%

Interferon Receptor Signaling in Malignancy: A Network of Cellular Pathways Defining Biological Outcomes

Fish

Platanias

2014

Molecular Cancer Research

View full text Add to dashboard Cite

Interferons (IFNs) are cytokines with important anti-proliferative activity and exhibit key roles in immune surveillance against malignancies. Early work initiated over 3 decades ago led to the discovery of IFN receptor activated Jak-Stat pathways and provided important insights into mechanisms for transcriptional activation of interferon stimulated genes (ISGs) that mediate IFN-biological responses. Since then, additional evidence has established critical roles for other receptor activated signaling pathways in the induction of IFN-activities. These include MAPK pathways, mTOR cascades and PKC pathways. In addition, specific microRNAs (miRNAs) appear to play a significant role in the regulation of IFN-signaling responses. This review focuses on the emerging evidence for a model in which IFNs share signaling elements and pathways with growth factors and tumorigenic signals, but engage them in a distinctive manner to mediate anti-proliferative and antiviral responses.

show abstract

Role of PKCδ in IFN-γ-inducible CIITA gene expression☆

Cited by 16 publications

References 45 publications

The IFN‐γ‐induced transcriptional program of the CIITA gene is inhibited by statins

The IFN‐γ‐induced transcriptional program of the CIITA gene is inhibited by statins

Mitogen-activated Protein Kinase ERK1/2 Regulates the Class II Transactivator

Interferon Receptor Signaling in Malignancy: A Network of Cellular Pathways Defining Biological Outcomes

Contact Info

Product

Resources

About