title: Inhibition of Transient Receptor Potential Channel Mucolipin-1 (TRPML1) by Lysosomal Adenosine Involved in Severe Combined Immunodeficiency Diseases.
abstract: Impaired adenosine homeostasis has been associated with numerous human diseases. Lysosomes are referred to as the cellular recycling centers that generate adenosine by breaking down nucleic acids or ATP. Recent studies have suggested that lysosomal adenosine overload causes lysosome defects that phenocopy patients with mutations in transient receptor potential channel mucolipin-1 (TRPML1), a lysosomal Ca2+channel, suggesting that lysosomal adenosine overload may impair TRPML1 and then lead to subsequent lysosomal dysfunction. In this study, we demonstrate that lysosomal adenosine is elevated by deleting adenosine deaminase (ADA), an enzyme responsible for adenosine degradation. We also show that lysosomal adenosine accumulation inhibits TRPML1, which is rescued by overexpressing ENT3, the adenosine transporter situated in the lysosome membrane. Moreover, ADA deficiency results in lysosome enlargement, alkalinization, and dysfunction. These are rescued by activating TRPML1. Importantly, ADA-deficient B-lymphocytes are more vulnerable to oxidative stress, and this was rescued by TRPML1 activation. Our data suggest that lysosomal adenosine accumulation impairs lysosome function by inhibiting TRPML1 and subsequently leads to cell death in B-lymphocytes. Activating TRPML1 could be a new therapeutic strategy for those diseases.
authors.affiliation: Departments of Physiology and Biophysics.
authors.forename: Xi Zoë
authors.initials: XZ
authors.lastname: Zhong
authors.affiliation: Departments of Physiology and Biophysics.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Departments of Physiology and Biophysics; Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Cytology and Genetics, Northeast Normal University, Changchun, 130024 Jilin, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Sun
authors.affiliation: Departments of Physiology and Biophysics.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Dong
authors.affiliation: Departments of Physiology and Biophysics.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Biochemistry and Molecular Biology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Aditya
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Biochemistry and Molecular Biology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, Nova Scotia B3H 4R2, Canada; Department of Chemistry, Dalhousie University, 6274 Coburg Road, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Rainey
authors.affiliation: Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Cytology and Genetics, Northeast Normal University, Changchun, 130024 Jilin, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Departments of Physiology and Biophysics. Electronic address: xpdong@dal.ca.
authors.forename: Xian-Ping
authors.initials: XP
authors.lastname: Dong
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: C416674:MCOLN1 protein, human; D050051:Transient Receptor Potential Channels; D000243:Adenosine Deaminase; D000241:Adenosine; D002118:Calcium
keywords: TRPML1; adenosine; calcium; calcium channel; lysosomal Ca2+; lysosome; trafficking