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Citrullination of inhibitor of growth 4 (ING4) by peptidylarginine deminase 4 (PAD4) disrupts the interaction between ING4 and p53.

ABSTRACT: Gene expression is regulated by a number of interrelated posttranslational modifications of histones, including citrullination. For example, peptidylarginine deminase 4 (PAD4) converts peptidyl arginine to citrulline in histone H3 and can repress gene expression. However, regulation of gene expression through citrullination of non-histone proteins is less well defined. Herein, we identify a tumor suppressor protein, inhibitor of growth 4 (ING4), as a novel non-histone substrate of PAD4. ING4 is known to bind p53 via its nuclear localization signal (NLS) region and to enhance transcriptional activity of p53. We show that PAD4 preferentially citrullinates ING4 in the same NLS region and thereby disrupts the interaction between ING4 and p53. A citrulline-mimicking Arg-NLS-Gln ING4 mutant, which has all Arg residues in the NLS mutated to Gln, loses its affinity for p53, can no longer promote p53 acetylation, and results in repression of downstream p21 expression. In addition, we found that citrullination leads to increased susceptibility of ING4 to degradation, likely impacting p53-independent pathways as well. These findings elucidate an interaction between posttranslational citrullination, acetylation, and methylation and highlight an unusual mechanism whereby citrullination of a non-histone protein impacts gene regulation.

SUBMITTER: Guo Q

PROVIDER: S-EPMC3089551 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Citrullination of inhibitor of growth 4 (ING4) by peptidylarginine deminase 4 (PAD4) disrupts the interaction between ING4 and p53.

Guo Qin Q Fast Walter W

The Journal of biological chemistry 20110322 19

Gene expression is regulated by a number of interrelated posttranslational modifications of histones, including citrullination. For example, peptidylarginine deminase 4 (PAD4) converts peptidyl arginine to citrulline in histone H3 and can repress gene expression. However, regulation of gene expression through citrullination of non-histone proteins is less well defined. Herein, we identify a tumor suppressor protein, inhibitor of growth 4 (ING4), as a novel non-histone substrate of PAD4. ING4 is ...[more]

PMID: 21454715

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Project description:In rheumatoid arthritis, an autoimmune inflammatory arthritis, citrullinated proteins are targeted by autoantibodies and thus thought to drive disease. Neutrophil extracellular traps (NETs) are a source of citrullinated proteins and are increased in rheumatoid arthritis and therefore also implicated in disease pathogenesis. However, not all NETs are citrullinated. One theory aiming to clarify the intersection of citrullination, NETs, and rheumatoid arthritis suggests that specific stimuli induce different types of NETs defined by citrullination status. However, most studies do not evaluate uncitrullinated NETs, only citrullinated or total NETs. Further, the requirement for peptidylarginine deiminase (PAD) 2 and 4, two important citrullinating enzymes in neutrophils and rheumatoid arthritis, in the formation of different NETs has not been clearly defined. To determine if specific stimulants induce citrullinated or uncitrullinated NETs and if those structures require PAD2 or PAD4, human and murine neutrophils, including from PAD4-/- and PAD2-/- mice, were stimulated in vitro and NETs imaged and quantified. In humans, phorbol myristate acetate (PMA), ionomycin, monosodium urate (MSU), and Candida albicans induced NETs with MSU and C. albicans inducing primarily citrullinated, PMA primarily uncitrullinated, and ionomycin a mix of NETs. Only ionomycin and C. albicans were strong inducers of NETs in mice with ionomycin-induced NETs mostly citrullinated and C. albicans-induced NETs a mix of citrullinated and uncitrullinated. Interestingly, no stimulus induced exclusively citrullinated or uncitrullinated NETs. Further, PAD4 was required for citrullinated NETs only, whereas PAD2 was not required for either NET in mice. Therefore, specific stimuli induce varying proportions of both citrullinated and uncitrullinated NETs with different requirements for PAD4. These findings highlight the complexity of NET formation and the need to further define the mechanisms by which different NETs form and their implications for autoimmune disease.

Dataset Information

Citrullination of inhibitor of growth 4 (ING4) by peptidylarginine deminase 4 (PAD4) disrupts the interaction between ING4 and p53.

Publications

Citrullination of inhibitor of growth 4 (ING4) by peptidylarginine deminase 4 (PAD4) disrupts the interaction between ING4 and p53.

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