title: PCSK6-mediated corin activation is essential for normal blood pressure.
abstract: Hypertension is the most common cardiovascular disease, afflicting >30% of adults. The cause of hypertension in most individuals remains unknown, suggesting that additional contributing factors have yet to be discovered. Corin is a serine protease that activates the natriuretic peptides, thereby regulating blood pressure. It is synthesized as a zymogen that is activated by proteolytic cleavage. CORIN variants and mutations impairing corin activation have been identified in people with hypertension and pre-eclampsia. To date, however, the identity of the protease that activates corin remains elusive. Here we show that proprotein convertase subtilisin/kexin-6 (PCSK6, also named PACE4; ref. 10) cleaves and activates corin. In cultured cells, we found that corin activation was inhibited by inhibitors of PCSK family proteases and by small interfering RNAs blocking PCSK6 expression. Conversely, PCSK6 overexpression enhanced corin activation. In addition, purified PCSK6 cleaved wild-type corin but not the R801A variant that lacks the conserved activation site. Pcsk6-knockout mice developed salt-sensitive hypertension, and corin activation and pro-atrial natriuretic peptide processing activity were undetectable in these mice. Moreover, we found that CORIN variants in individuals with hypertension and pre-eclampsia were defective in PCSK6-mediated activation. We also identified a PCSK6 mutation that impaired corin activation activity in a hypertensive patient. Our results indicate that PCSK6 is the long-sought corin activator and is important for sodium homeostasis and normal blood pressure.
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Shenghan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Pengxiu
authors.initials: P
authors.lastname: Cao
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.|Key Laboratory of Thrombosis and Hemostasis, Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Ningzheng
authors.initials: N
authors.lastname: Dong
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Jianhao
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Chunyi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Junhua
authors.initials: J
authors.lastname: Yang
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Martelli
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Sathyamangla V
authors.initials: SV
authors.lastname: Naga Prasad
authors.affiliation: Department of Internal Medicine (Rheumatology), Rush University Medical Center, Chicago, Illinois, USA.|Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Rachel E
authors.identifier: http://orcid.org/0000-0002-4486-5757
authors.initials: RE
authors.lastname: Miller
authors.affiliation: Department of Internal Medicine (Rheumatology), Rush University Medical Center, Chicago, Illinois, USA.|Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Malfait
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.|Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000818:Animals; D001794:Blood Pressure; D006224:Cricetinae; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D043484:Proprotein Convertases / Q000235:genetics / Q000502:physiology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000502:physiology*
chemical_list: C119812:CORIN protein, human; C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases