TY - JOUR
T1 - Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility
AU - Tanikawa, Chizu
AU - Ueda, Koji
AU - Suzuki, Akari
AU - Iida, Aritoshi
AU - Nakamura, Ryoichi
AU - Atsuta, Naoki
AU - Tohnai, Genki
AU - Sobue, Gen
AU - Saichi, Naomi
AU - Momozawa, Yukihide
AU - Kamatani, Yoichiro
AU - Kubo, Michiaki
AU - Yamamoto, Kazuhiko
AU - Nakamura, Yusuke
AU - Matsuda, Koichi
N1 - Funding Information:
This work was supported partially by a grant from the Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology - Japan to K.M. and C.T., a grant from the Japan Agency for Medical Research and Development to K.M. (16H01566 and 25134707) and C.T. (25710009), a grant from the Ministry of Health, Labour and Welfare of Japan to K.M., and a grant from the Takeda Science Foundation to K.M. and C.T. We also thank the members of the BioBank Japan Project, which is supported by the Ministry of Education, Culture, Sports, Science and Technology - Japan and the Japan Agency for Medical Research and Development . JaCALS was supported by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development , Health and Labor Sciences Research grants, and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology - Japan .
Publisher Copyright:
© 2018 The Author(s)
PY - 2018/2/6
Y1 - 2018/2/6
N2 - Recent proteome analyses have provided a comprehensive overview of various posttranslational modifications (PTMs); however, PTMs involving protein citrullination remain unclear. We performed a proteomic analysis of citrullinated proteins, and we identified more than 100 PAD4 (peptidyl arginine deiminase 4) substrates. Approximately one-fifth of the PAD4 substrates contained an RG/RGG motif, and PAD4 competitively inhibited the methylation of the RGG motif in FET proteins (FUS, EWS, and TAF15) and hnRNPA1, which are causative genes for ALS (amyotrophic lateral sclerosis). PAD4-mediated citrullination significantly inhibited the aggregation of FET proteins, a frequently observed feature in neurodegenerative diseases. FUS protein levels in arsenic-induced stress granules were significantly increased in Padi4 −/− mouse embryonic fibroblasts (MEFs). Moreover, rs2240335 was associated with low expression of PADI4 in the brain and a high risk of ALS (p = 0.0381 and odds ratio of 1.072). Our findings suggest that PAD4-mediated RGG citrullination plays a key role in protein solubility and ALS pathogenesis. Tanikawa et al. report a role of PAD4 in protein aggregation and ALS. Proteome analysis revealed the RG/RGG motif as a consensus sequence for PAD4-mediated citrullination. PAD4 inhibits the methylation and aggregation of FET proteins. rs2240335 in PADI4 is associated with low PADI4 expression and a high risk of ALS.
AB - Recent proteome analyses have provided a comprehensive overview of various posttranslational modifications (PTMs); however, PTMs involving protein citrullination remain unclear. We performed a proteomic analysis of citrullinated proteins, and we identified more than 100 PAD4 (peptidyl arginine deiminase 4) substrates. Approximately one-fifth of the PAD4 substrates contained an RG/RGG motif, and PAD4 competitively inhibited the methylation of the RGG motif in FET proteins (FUS, EWS, and TAF15) and hnRNPA1, which are causative genes for ALS (amyotrophic lateral sclerosis). PAD4-mediated citrullination significantly inhibited the aggregation of FET proteins, a frequently observed feature in neurodegenerative diseases. FUS protein levels in arsenic-induced stress granules were significantly increased in Padi4 −/− mouse embryonic fibroblasts (MEFs). Moreover, rs2240335 was associated with low expression of PADI4 in the brain and a high risk of ALS (p = 0.0381 and odds ratio of 1.072). Our findings suggest that PAD4-mediated RGG citrullination plays a key role in protein solubility and ALS pathogenesis. Tanikawa et al. report a role of PAD4 in protein aggregation and ALS. Proteome analysis revealed the RG/RGG motif as a consensus sequence for PAD4-mediated citrullination. PAD4 inhibits the methylation and aggregation of FET proteins. rs2240335 in PADI4 is associated with low PADI4 expression and a high risk of ALS.
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U2 - 10.1016/j.celrep.2018.01.031
DO - 10.1016/j.celrep.2018.01.031
M3 - Article
C2 - 29425503
AN - SCOPUS:85041727853
SN - 2211-1247
VL - 22
SP - 1473
EP - 1483
JO - Cell Reports
JF - Cell Reports
IS - 6
ER -