Abstract LB-036: Citrullinome analysis identifies the role of PADI4 in regulating RNA processing and tumor immunogenicity

Abstract

Abstract Recent proteome analyses have provided a comprehensive overview of various posttranscriptional modifications (PTM); however, PTMs involving protein citrullination remain unclear. Thus, we performed a proteomic analysis of citrullinated proteins and identified more than 100 PADI4 substrates, the majority of which are related to RNA processing and protein translation. Citrullination of RBMX (RNA binding motif protein, X-linked) inhibited the interaction with other hnRNP family members. RNA sequence analyses revealed altered splicing patterns in more than 300 genes in bone marrow cells in Padi4-/- mice. Approximately one-fifth of the PADI4 substrates contained an RG/RGG motif, and citrullination by PADI4 competitively inhibited the methylation of the RGG motif in FET proteins (EWS and TAF15). In addition, PADI4-mediated citrullination inhibited the aggregation of TAF15 proteins, which is a frequently-observed feature in neurodegenerative diseases, such as ALS. An antibody against citrullinated RGG motifs was observed in 11.5% (27 among 234) of serum samples from patients with HCV-related hepatocellular carcinoma, and female patients with high serum antibody exhibited poor prognosis. Our findings imply that PADI4-mediated citrullination plays a key role in RNA processing, protein aggregation and tumor immunogenicity, and suggest that PADI4 activation has potential therapeutic implications for neurodegenerative disease and cancer immunotherapy. Citation Format: Chizu Tanikawa, Koichi Matsuda. Citrullinome analysis identifies the role of PADI4 in regulating RNA processing and tumor immunogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-036. doi:10.1158/1538-7445.AM2017-LB-036