Cryptides: Identification of novel cryptides and elucidation of their physiological roles

• Project/Area Number: 25350971
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biomolecular chemistry
• Research Institution: Nagahama Institute of Bio-Science and Technology
• Principal Investigator: Mukai Hidehito 長浜バイオ大学, バイオサイエンス学部, 准教授 (20251027)
• Co-Investigator(Kenkyū-buntansha): KISO Yoshiaki 長浜バイオ大学, バイオサイエンス学部, 客員教授 (40089107)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 生理活性ペプチド / クリプタイド / マイトクリプタイド / Gタンパク質共役受容体 / 好中球 / 自然免疫 / 中和抗体 / 拮抗阻害ペプチド / 自然炎症 / 拮抗阻害薬

Outline of Final Research Achievements

Recently, we have purified and identified novel neutrophil-activating cryptides, including mitocryptide-1 (MCT-1) and mitocryptide-2 (MCT-2), which were derived from mitochondrial cytochrome c oxidase subunit VIII and cytochrome b, respectively, from healthy porcine hearts. We also found the presence of many neutrophil-activating peptides produced from various mitochondrial proteins. However, physiological roles of those mitocryptides and their involvements in various diseases associated with the neutrophilic functions have not been elucidated yet. Here, we identified 15 novel neutrophil-activating peptides derived from various mitochondrial proteins. We also developed competitive antagonists against MCT-2 and MCT-3 and specific neutralizing antibodies against the functions induced by MCT-1 and MCT-2. Moreover, it was indicated that these neutrophil-activating peptides including MCT-1 and MCT-2 involve neutrophil infiltration in vivo.

Research Products

• [Journal Article] Mitocryptide-3: characterization of its receptor molecules (2016)
  • Author(s): Marutani, T., Nakashima, K., Tsutsumi, K., Hattori, T., Nishino, K., Shimizu, T., Kiso, Y., and Mukai, H.
  • Journal Title: Peptide Science Volume: 2015 Pages: 251-252
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of mitocryptide-1 on inflammatory cells in mice (2016)
  • Author(s): Hattori, T., Morikawa, H., Marutani, T., Tsutsumi, K., Kiso, Y., and Mukai, H.
  • Journal Title: Peptide Science Volume: 2015 Pages: 253-254
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mitochondrial protein-derived cryptides: are endogenous N-formylated peptides including mitocryptide-2 components of mitochondrial damage-associated molecular patterns? (2016)
  • Author(s): Marutani, T., Hattori, T., Tsutsumi, K., Koike, Y., Harada, A., Noguchi, K., Kiso, Y., and Mukai, H.
  • Journal Title: Biopolymers: Peptide Science Volume: 106 Issue: 4 Pages: 580-587
  • DOI: 10.1002/bip.22788
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Successful acquisition of a neutralizing monoclonal antibody against a novel neutrophil-activating peptide, mitocryptide-1 (2015)
  • Author(s): Hattori, T., Nakashima, K., Marutani, T., Kiso, Y., Nishi, Y., and Mukai, H.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 463 Issue: 1-2 Pages: 54-59
  • DOI: 10.1016/j.bbrc.2015.05.016
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Structure-activity relationships of mitocryptide-3 on the activation of neutrophilic cells (2015)
  • Author(s): Nakashima, K., Marutani, T., Hattori, T., Noguchi, K., Kiso, Y., and Mukai, H.
  • Journal Title: Peptide Science Volume: 2014 Pages: 175-176
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Investigation of ligand recognition mechanisms of receptors for mitocryptide-1 (2015)
  • Author(s): Tsutsumi, K., Marutani, T., Hattori, T., Kiso, Y., and Mukai, H.
  • Journal Title: Peptide Science Volume: 2014 Pages: 177-178
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mitocryptide-2: structure-activity relationships for the elucidation of ligand recognition mechanisms of formyl-peptide receptor like 1 (2015)
  • Author(s): Marutani, T., Hattori, T., Koike, Y., Harada, A., Watanabe, K., Kiso, Y., and Mukai, H.
  • Journal Title: Peptides Volume: 2014 Pages: 6-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Functional analysis of mitocryptides with their neutralizing monoclonal antibodies (2015)
  • Author(s): Hattori, T., Araki, R., Watanabe, K., Marutani, T., Nakashima, K., Nishi, Y., Kiso, Y., and Mukai, H.
  • Journal Title: Peptides Volume: 2014 Pages: 360-361
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Successful acquisition of a neutralizing monoclonal antibody against a novel neutrophil-activating peptide, mitocryptide-1 (2015)
  • Author(s): Hattori, T., Nakashima, K., Marutani, T., Kiso, Y., Nishi, Y., and Hidehito Mukai, H.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mitocryptides: Elucidation of their biological functions with their monoclonal antibodies (2014)
  • Author(s): Hattori, T., Araki, R., Nakashima, K., Marutani, T., Ogino, S., Koike, Y., Hirooka, Y., Miyake, N., Murata, K., Watanabe, K., Kiso, Y., Nishi, Y., and Mukai, H.
  • Journal Title: Peptide Science Volume: 2013 Pages: 247-248
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Endogenous N-formylated cryptides: Investigation of their biological functions (2014)
  • Author(s): Marutani, T., Hattori, T., Koike, Y., Harada, A., Watanabe, K., Kiso, Y., and Mukai, H.
  • Journal Title: Peptide Science Volume: 2013 Pages: 249-250
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Aggregation inhibitor of amyloid-β peptide based on O-acyl isopeptide (2014)
  • Author(s): Kawashima, H., Sohma, Y., Nakanishi, T., Kitamura, H., Mukai, H., Yamashita, M., Akaji, K., and Kiso, Y.
  • Journal Title: Peptide Science Volume: 2013 Pages: 101-104
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] クリプタイドータンパク質に隠された新しい生理活性ペプチド (2014)
  • Author(s): 服部竜弥，向井秀仁
  • Journal Title: 日本薬理学雑誌 Volume: 144 Pages: 234-238
  • NAID: 130004704238
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] クリプタイド：タンパク質に隠された新しい機能ペプチド (2013)
  • Author(s): 向井秀仁，木曽良明
  • Journal Title: バイオサイエンスとインダストリー Volume: 71 Pages: 18-22
  • NAID: 10031140296
  • Peer Reviewed
• [Journal Article] Comparative properties of Aβ1-42, Aβ11-42, and [Pyr^<11>]Aβ11-42 generated from O-acyl isopeptides (2013)
  • Author(s): 相馬洋平
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 23巻 Issue: 5 Pages: 1326-1329
  • DOI: 10.1016/j.bmcl.2012.12.082
  • Peer Reviewed
• [Journal Article] Functional analysis of mitocryptides with their monoclonal antibodies (2013)
  • Author(s): Hattori, T., Shirota, S., Marutani, T., Kiso, Y., Nishi, Y., and Mukai, H.
  • Journal Title: Peptide Science Volume: 2012 Pages: 277-278
  • NAID: 10031161627
  • Peer Reviewed
• [Journal Article] A new class of aggregation inhibitor of amyloid-β peptide based on an O-acyl isopeptide. (2013)
  • Author(s): 川島 浩之
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 21 Issue: 21 Pages: 6323-6327
  • DOI: 10.1016/j.bmc.2013.08.062
  • Peer Reviewed
• [Journal Article] Identification and structure-activity studies of novel cryptides hidden in mitochondrial proteins (2013)
  • Author(s): Mukai, H., Hokari, Y., Seki, T., Fukamizu, A., and Kiso, Y.
  • Journal Title: Peptides: Across the Pacific Volume: 2013 Pages: 314-315
  • Peer Reviewed
• [Presentation] マイトクリプタイド：ミトコンドリアタンパク質配列に隠された一群の免疫調節因子 (2016)
  • Author(s): 向井秀仁、服部竜弥、丸谷飛之、堤光己、木曽良明
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2016-03-29
  • Invited
• [Presentation] Cryptides: endogenous bioactive peptides hidden in protein structures (2016)
  • Author(s): Mukai, H., and Kiso, Y.
  • Organizer: The 8th Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: Suita, Osaka
  • Year and Date: 2016-01-21
  • Int'l Joint Research / Invited
• [Presentation] Mitocryptides: candidate factors for neutrophil-activating peptides in mitochondrial DAMPs (2016)
  • Author(s): Hattori, T., Morikawa, H., Yamada, T., Marutani, T., Kiso, Y., and Mukai, H.
  • Organizer: The 8th Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: Suita, Osaka
  • Year and Date: 2016-01-21
  • Int'l Joint Research
• [Presentation] Identification of receptor molecules for mitocryptides, a novel family of neutrophil-activating peptides derived from mitochondrial proteins (2016)
  • Author(s): Marutani, T., Nakashima, K., Tsutsumi, K., Hattori, T., Nishino, K., Shimizu, T., Kiso, Y., and Mukai, H.
  • Organizer: The 8th Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: Suita, Osaka
  • Year and Date: 2016-01-21
  • Int'l Joint Research
• [Presentation] 新規好中球活性化ペプチド、mitocryptide-3に対する受容体の同定 (2015)
  • Author(s): 丸谷飛之、中島健太、堤光己、服部竜弥、西野弘大、清水稔弘、木曽良明、向井秀仁
  • Organizer: 第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2015-12-03
• [Presentation] マイトクリプタイドが免疫細胞に及ぼす影響の解析 (2015)
  • Author(s): 服部竜弥、森川広樹、丸谷飛之、堤光己、西義介、木曽良明、向井秀仁
  • Organizer: 第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2015-12-02
• [Presentation] 新規好中球活性化ペプチド、マイトクリプタイド-1の構造活性相関の検討 (2015)
  • Author(s): 堤光己、丸谷飛之、服部竜弥、清水稔弘、木曽良明、向井秀仁
  • Organizer: 第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2015-12-02
• [Presentation] マイトクリプタイド-3：受容体分子の解析 (2015)
  • Author(s): 丸谷飛之、中島健太、堤光己、服部竜弥、西野弘大、清水稔弘、木曽良明、向井秀仁
  • Organizer: ペプチド討論会
  • Place of Presentation: 神奈川県平塚市
  • Year and Date: 2015-11-17
• [Presentation] マイトクリプタイド-1のマウス免疫細胞に対する効果 (2015)
  • Author(s): 服部竜弥、森川広樹、丸谷飛之、堤光己、木曽良明、向井秀仁
  • Organizer: ペプチド討論会
  • Place of Presentation: 神奈川県平塚市
  • Year and Date: 2015-11-16
• [Presentation] 一群の新しい生理活性ペプチド、クリプタイド：からだをコントロールするシャドープレイヤー (2015)
  • Author(s): 向井秀仁
  • Organizer: 日本ペプチド学会市民フォーラム２０１５
  • Place of Presentation: 神奈川県平塚市
  • Year and Date: 2015-11-15
  • Invited
• [Presentation] Mitocryptides: structure-activity relationships of a novel family of neutrophil-activating peptides (2015)
  • Author(s): Mukai, H.
  • Organizer: 5th Modern Solid Phase Peptide Synthesis and its Application Symposium
  • Place of Presentation: Queensland, Australia
  • Year and Date: 2015-10-23
  • Int'l Joint Research / Invited
• [Presentation] Mitocryptides: physiological and pathophysiological significance of a novel family of neutrophil-activating peptides (2015)
  • Author(s): Mukai, H.
  • Organizer: 14th International Congress on Amino Acids, Peptides and Proteins
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2015-08-04
  • Int'l Joint Research / Invited
• [Presentation] Cryptides and their accumulative signaling mechanisms for novel therapeutic targets (2015)
  • Author(s): Mukai, H.
  • Organizer: 7th Annual AisiaTIDES
  • Place of Presentation: Osaka
  • Year and Date: 2015-03-03 – 2015-03-05
  • Invited
• [Presentation] マイトクリプタイド-3の好中球様細胞活性化における構造活性相関の検討 (2014)
  • Author(s): 中島健太、丸谷飛之、服部竜弥、野口公輔、木曽良明、向井秀仁
  • Organizer: 第51回ペプチド討論会
  • Place of Presentation: 徳島
  • Year and Date: 2014-10-22 – 2014-10-24
• [Presentation] マイトクリプタイド-1受容体のリガンド認識機構の検討 (2014)
  • Author(s): 堤光己、丸谷飛之、服部竜弥、木曽良明、向井秀仁
  • Organizer: 第51回ペプチド討論会
  • Place of Presentation: 徳島
  • Year and Date: 2014-10-22 – 2014-10-24
• [Presentation] 好中球活性化ペプチド、マイトクリプタイド-1に対する中和抗体の取得とそれを用いた生理機能解析 (2014)
  • Author(s): 服部竜弥、荒木良太、福井茜音、中島健太、丸谷飛之、木曽良明、西義介、向井秀仁
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] 新規の内因性ホルミルペプチドによる好中球活性化機序 (2014)
  • Author(s): 丸谷飛之、堤光己、服部竜弥、小池裕介、原田明彦、渡辺建佑、野口公輔、山中陽介、木曽良明、向井秀仁
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] 一群の新規好中球活性化ペプチド、マイトクリプタイドに対する受容体のリガンド認識機構の解明 (2014)
  • Author(s): 中島健太、丸谷飛之、服部竜弥、青木慎一郎、梅田龍平、仁本義章、野口公輔、福井茜音、山中陽介、木曽良明、向井秀仁
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] Mitocryptides: Physiological Significance of a Novel Family of Neutrophil-Activating Peptides (2014)
  • Author(s): Mukai, H., Hattori, T., Marutani, T., Nakashima, K., Tsutsumi, K., and Kiso, Y.
  • Organizer: 15th German-Japanese Symposium on Peptide Science
  • Place of Presentation: Boppard, Germany
  • Year and Date: 2014-09-07 – 2014-09-09
  • Invited
• [Presentation] Mitocryptide-2: structure-activity relationships for the elucidation of ligand recognition mechanisms of Formyl-peptide receptor like-1 (2014)
  • Author(s): Marutani, T., Hattori, T., Koike, Y., Harada, A., Watanabe, K., Kiso, Y., and Mukai, H.
  • Organizer: 33rd European Peptide Symposium
  • Place of Presentation: Sofia, Bulgaria
  • Year and Date: 2014-08-31 – 2014-09-05
  • Invited
• [Presentation] Functional analysis of mitocryptides with their neutralizing monoclonal antibodies (2014)
  • Author(s): Hattori, T., Araki, R., Watanabe, K., Marutani, T., Nakashima, K., Nishi, Y., Kiso, Y., and Mukai, H.
  • Organizer: 33rd European Peptide Symposium
  • Place of Presentation: Sofia, Bulgaria
  • Year and Date: 2014-08-31 – 2014-09-05
• [Presentation] 一群の新規好中球活性化ペプチド、マイトクリプタイドに対する特異的抗体を用いた生体機能解析 (2014)
  • Author(s): 服部竜弥、荒木良太、渡辺建佑、丸谷飛之、中島健太、西義介、木曽良明、向井秀仁
  • Organizer: 日本ケミカルバイオロジー学会 第9回年会
  • Place of Presentation: 大阪
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] ミトコンドリアタンパク質に由来する内因性N-ホルミル化クリプタイドの生体機能解析 (2014)
  • Author(s): 丸谷飛之、服部竜弥、小池祐介、原田明彦、渡辺建佑、堤光己、野口公輔、木曽良明、向井秀仁
  • Organizer: 日本ケミカルバイオロジー学会第9回年会
  • Place of Presentation: 大阪
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] クリプタイド：その存在意義と産業的応用 (2013)
  • Author(s): 向井秀仁
  • Organizer: 新科学技術推進協会ライフサイエンス技術部会・材料分科会講演会
  • Place of Presentation: 東京
  • Invited
• [Presentation] Identification and Structure-Activity Studies of Novel Cryptides Hidden in Mitochondrial Proteins (2013)
  • Author(s): Mukai, H., Hokari, Y., Seki, T., Fukamizu, A., and Kiso, Y.
  • Organizer: 6th International Peptide Symposium / 23rd American Peptide Symposium
  • Place of Presentation: Big Island, Hawaii, USA
• [Presentation] 好中球活性化ペプチド、マイトクリプタイドに対するモノクローナル抗体の作製とそれを用いた生理機能解析 (2013)
  • Author(s): 服部竜弥, 荒木良太, 丸谷飛之, 荻野智史, 小池祐介, 廣岡佑一, 木曽良明, 西義介, 向井秀仁
  • Organizer: 日本生化学会第86回大会
  • Place of Presentation: 横浜
• [Presentation] ミトコンドリアタンパク質に由来する内因性ホルミルペプチドの生体機能解析 (2013)
  • Author(s): 丸谷飛之, 服部竜弥, 木曽良明, 向井秀仁
  • Organizer: 日本生化学会第86回大会
  • Place of Presentation: 横浜
• [Presentation] クリプタイドと創薬－－タンパク質に隠された新しい生理活性ペプチド、クリプタイドの系統的探索および生体機能の解析と創薬への応用 (2013)
  • Author(s): 向井秀仁
  • Organizer: 生命分子機能研究会2013学術集会
  • Place of Presentation: 長浜
  • Invited
• [Presentation] Systematic identification of neutrophil-activating cryptides utilizing multiple solid-phase peptide synthesis (2013)
  • Author(s): Mukai, H., Hattori, T., Araki, R., Nakashima, K., Marutani, T., and Kiso, Y.
  • Organizer: 4th Modern SPPS and Its Applications Symposium
  • Place of Presentation: Kobe
• [Presentation] O-Acyl Isopeptide : A New Class of Aggregation Inhibitor of Amyloid β Peptide (2013)
  • Author(s): Ohno, S., Kawashima, H., Sohma, Y., Nakanishi, T., Kitamura, H., Mukai, H., Yamashita, M., Akaji, K., and Kiso, Y.
  • Organizer: 4th Modern SPPS & Its Applications Symposium
  • Place of Presentation: Kobe
• [Presentation] Mitocryptides: Elucidation of their biological functions with their monoclonal antibodies (2013)
  • Author(s): Hattori, T., Araki, R., Nakashima, K., Marutani, T., Ogino, S., Koike, Y., Hirooka, Y., Miyake, N., Murata, K., Watanabe, K., Kiso, Y., Nishi, Y., and Mukai, H.
  • Organizer: 4th Asia-Pacific International Peptide Symposium / 50th Japanese Peptide Symposium
  • Place of Presentation: Suita, Osaka
• [Presentation] Endogenous N-formylated cryptides: Investigation of their biological functions (2013)
  • Author(s): Marutani, T., Hattori, T., Koike, Y., Harada, A., Watanabe, K., Kiso, Y., and Mukai, H.
  • Organizer: 4th Asia-Pacific International Peptide Symposium / 50th Japanese Peptide Symposium
  • Place of Presentation: Suita, Osaka
• [Presentation] Aggregation inhibitor of amyloid-β peptide based on O-acyl isopeptide (2013)
  • Author(s): Kawashima, H., Sohma, Y., Nakanishi, T., Kitamura, H., Mukai, H., Yamashita, M., Akaji, K., and Kiso, Y.
  • Organizer: 4th Asia-Pacific International Peptide Symposium / 50th Japanese Peptide Symposium
  • Place of Presentation: Suita, Osaka
• [Presentation] 内因性N-ホルミルペプチドの生体機能の検討 (2013)
  • Author(s): 向井秀仁
  • Organizer: 関西ペプチドセミナー
  • Place of Presentation: 神戸
• [Book] ホルモンから見た生命現象と進化第７巻第４章 (2016)
  • Author(s): 向井秀仁
  • Publisher: 裳華房
• [Remarks] 長浜バイオ大学ペプチド科学研究室
  • URL: http://b-lab.nagahama-i-bio.ac.jp/~h_mukai/
• [Remarks] 長浜バイオ大学教員紹介
  • URL: http://www.nagahama-i-bio.ac.jp/research/
• [Remarks] 長浜バイオ大学ペプチド科学研究室
  • URL: http://b-lab.nagahama-i-bio.ac.jp/~h_mukai/
• [Remarks] 長浜バイオ大学 教員紹介
  • URL: http://www.nagahama-i-bio.ac.jp/guide/kyoin/detail/post-5.html