Regulating the Activity of Class II Transactivator by Posttranslational Modifications: Exploring the Possibilities

Wu, Xiaoyan; Kong, Xu; Luchsinger, Larry L.; Smith, Barbara D.; Xu, Yong

doi:10.1128/mcb.00661-09

Cited by 33 publications

(32 citation statements)

References 40 publications

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“…CIITA activity can be modulated by its post-translational modifications11. We postulated that PRMT1 might directly methylate CIITA to influence its activity.…”

Section: Resultsmentioning

confidence: 99%

“…Whereas CIITA loss-of-function mutations leads to ineffectual MHC II transactivation and immunodeficiency, CIITA hyperactivation is associated with aberrant MHC II transactivation and chronic inflammation10. CIITA activity can be modulated at both transcriptional and post-translational levels11. Previously we have shown that several different post-translational modifications contribute to differential modulation of CIITA activity.…”

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confidence: 99%

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Protein arginine methyltransferase 1 (PRMT1) represses MHC II transcription in macrophages by methylating CIITA

Fan

et al. 2017

Sci Rep

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Efficient presentation of alien antigens triggers activation of T lymphocytes and robust host defense against invading pathogens. This pathophysiological process relies on the expression of major histocompatibility complex (MHC) molecules in antigen presenting cells such as macrophages. Aberrant MHC II transactivation plays a crucial role in the pathogenesis of atherosclerosis. Class II transactivator (CIITA) mediates MHC II induction by interferon gamma (IFN-γ). CIITA activity can be fine-tuned at the post-translational level, but the mechanisms are not fully appreciated. We investigated the role of protein arginine methyltransferase 1 (PRMT1) in this process. We report here that CIITA interacted with PRMT1. IFN-γ treatment down-regulated PRMT1 expression and attenuated PRMT1 binding on the MHC II promoter. Over-expression of PRMT1 repressed MHC II promoter activity while PRMT1 depletion enhanced MHC II transactivation. Mechanistically, PRMT1 methylated CIITA and promoted CIITA degradation. Therefore, our data reveal a previously unrecognized role for PRMT1 in suppressing CIITA-mediated MHC II transactivation.

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“…CIITA activity can be modulated by its post-translational modifications11. We postulated that PRMT1 might directly methylate CIITA to influence its activity.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Protein arginine methyltransferase 1 (PRMT1) represses MHC II transcription in macrophages by methylating CIITA

Fan

et al. 2017

Sci Rep

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“…In contrast, to our knowledge, this paper presents the first identification of a domain responsible for the nuclear export of CIITA. The specific import and export of CIITA is regulated by posttranslational modifications of CIITA (33), notably GTP binding, acetylation, phosphorylation, and the LRR in the COOH terminus. Binding of GTP to the GBD (aa 336-702) correlates with self-association and increased nuclear localization of CIITA (47,48,62) and increased transactivation of class II genes (49,63).…”

Section: Discussionmentioning

confidence: 99%

“…Structurally, CIITA is a member of the NLR/Caterpillar family of genes (32) and contains a multitude of regulatory domains, including an N-terminal acidic domain responsible for transactivation; a PST domain rich in proline, serine, and threonine residues that show susceptibility to phosphorylation by several different kinases; a GTP binding domain (GBD) involved in regulating self-association, nuclear localization, and promoter transactivation; and a leucine-rich region (LRR) common to all NLR/Caterpillar proteins that modulates complex formation, nuclear localization, and CIITA-mediated gene activation (28,30,33).…”

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confidence: 99%

Identification of a Nuclear Export Sequence in the MHC CIITA

Chiu

Gold

Fettig

et al. 2015

The Journal of Immunology

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Initiation of an immune response through expression of MHC class II and related genes is under the control of the CIITA. Normally found in both the cytoplasm and nucleus, CIITA is tightly controlled by a variety of posttranslational modifications as well as interactions with other nuclear and cytoplasmic factors, whereas disruption of this dual subcellular localization impairs CIITA functioning and expression of target genes. Although CIITA has well-defined domains necessary for its nuclear import, the region responsible for the translocation of CIITA from the nucleus has not been characterized. In this study, we identify a leucine-rich motif at residues 717–724 that bears strong homology to known nuclear export sequence (NES) domains. Mutation of this region renders CIITA insensitive to treatment with leptomycin B, an inhibitor of nuclear export, whereas fusion of this domain to a heterologous GFP is sufficient to induce its export to the cytoplasm or cause its retention in the nucleus following leptomycin B treatment. Point mutations of specific leucine residues within the NES disrupt the normal subcellular distribution of the full-length CIITA, impair its ability to interact with the nuclear export factor CRM1, and enhance CIITA-induced gene expression from an MHC class II gene promoter. IFN-γ stimulation of class II genes is further enhanced by inhibiting the nuclear export of endogenous CIITA. Collectively, these data demonstrate the first identification of a specific NES within CIITA and place it among the other protein domains that contribute to the posttranslational regulation of CIITA activity.

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“…Nevertheless, the inability of CIITA to interact with Tax in vitro cannot be ascribed to the incapacity of CIITA to self-associate in vitro , because, as mentioned above, the dimerization-deficient CIITAΔ253–410 mutant retains the ability to inhibit Tax-1 in vivo . Other modifications of CIITA, including acetylation, deacetylation, and ubiquitination (Spilianakis et al, 2000; Wu et al, 2009 and references therein), might have a major role in Tax-1-binding. Such PTMs have been reported to affect the interaction of CIITA with cellular factors involved in MHC-II transcription (Greer et al, 2003) and the recruitment of either corepressors or coactivators on different promoters (Xu et al, 2008; Wu et al, 2009).…”

Section: Ciita Targets Tax-1 and Tax-2 Transactivators To Inhibit Virmentioning

confidence: 99%

The MHC-II transactivator CIITA, a restriction factor against oncogenic HTLV-1 and HTLV-2 retroviruses: similarities and differences in the inhibition of Tax-1 and Tax-2 viral transactivators

Forlani¹,

Abdallah²,

Accolla³

et al. 2013

Front. Microbiol.

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The activation of CD4+ T helper cells is strictly dependent on the presentation of antigenic peptides by MHC class II (MHC-II) molecules. MHC-II expression is primarily regulated at the transcriptional level by the AIR-1 gene product CIITA (class II transactivator). Thus, CIITA plays a pivotal role in the triggering of the adaptive immune response against pathogens. Besides this well known function, we recently found that CIITA acts as an endogenous restriction factor against HTLV-1 (human T cell lymphotropic virus type 1) and HTLV-2 oncogenic retroviruses by targeting their viral transactivators Tax-1 and Tax-2, respectively. Here we review our findings on CIITA-mediated inhibition of viral replication and discuss similarities and differences in the molecular mechanisms by which CIITA specifically counteracts the function of Tax-1 and Tax-2 molecules. The dual function of CIITA as a key regulator of adaptive and intrinsic immunity represents a rather unique example of adaptation of host-derived factors against pathogen infections during evolution.

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Regulating the Activity of Class II Transactivator by Posttranslational Modifications: Exploring the Possibilities

Cited by 33 publications

References 40 publications

Protein arginine methyltransferase 1 (PRMT1) represses MHC II transcription in macrophages by methylating CIITA

Protein arginine methyltransferase 1 (PRMT1) represses MHC II transcription in macrophages by methylating CIITA

Identification of a Nuclear Export Sequence in the MHC CIITA

The MHC-II transactivator CIITA, a restriction factor against oncogenic HTLV-1 and HTLV-2 retroviruses: similarities and differences in the inhibition of Tax-1 and Tax-2 viral transactivators

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