A Mechanism of Release of Calreticulin from Cells During Apoptosis

JOURNAL OF MOLECULAR BIOLOGY

卷:401

Article

Tarr, Joanna M.¹  Young, Philip J.¹  Morse, Robert¹  Shaw, Debra J.¹  Haigh, Richard^1,3  Petrov, Peter G.²  Johnson, Steven J.⁴  Winyard, Paul G.¹  Eggleton, Paul¹ 

[1] Univ Exeter, Peninsula Med Sch, Exeter EX1 2LU, Devon, England

[2] Univ Exeter, Sch Phys, Exeter EX4 4QL, Devon, England

[3] Royal Devon & Exeter Fdn Trust Hosp, Princess Elizabeth Orthopaed Ctr, Exeter EX2 5DW, Devon, England

[4] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England

关键词: cell recognition;    calreticulin-phosphatidylserine interaction;    endoplasmic reticulum;    protein secretion;   

DOI  :  10.1016/j.jmb.2010.06.064

来源: Elsevier

【 摘 要 】

Calreticulin (CRT) is an endoplasmic reticulum (ER) chaperone responsible for glycoprotein folding and Ca2+ homeostasis. CRT also has extracellular functions, e.g. tumor and apoptotic cell recognition and wound healing, but the mechanism of CRT extracellular release is unknown. Cytosolic localization of CRT is determined by signal peptide and subsequent retrotranslocation of CRT into the cytoplasm. Here, we show that under apoptotic stress conditions, the cytosolic concentration of CRT increases and associates with phosphatidylserine (PS) in a Ca2+-dependent manner. PS distribution is regulated by aminophospholipid translocase (APLT), which maintains PS on the cytosolic side of the cell membrane. APLT is sensitive to redox modifications of its SH groups by reactive nitrogen species. During apoptosis, both CRT expression and the concentration of nitric oxide (NO) increase. By using S-nitroso-L-cysteine-ethyl-ester, an intracellular NO donor and inhibitor of APLT, we showed that PS and CRT externalization occurred together in an S-nitrosothiol-dependent and caspase-independent manner. Furthermore, the CRT and PS are relocated as punctate clusters on the cell surface. Thus, CRT induced nitrosylation and its externalization with PS could explain how CRT acts as a bridging molecule during apoptotic cell clearance. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

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