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STIM1 knock-down decreases the affinity of obinutuzumab for CD20 by altering CD20 localization to Triton-soluble membrane

Authors
 W Heo  ;  N Jin  ;  M S Park  ;  H-Y Kim  ;  S M Yoon  ;  J Lee  ;  J Y Kim 
Citation
 CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol.200(3) : 260-271, 2020-06 
Journal Title
 CLINICAL AND EXPERIMENTAL IMMUNOLOGY 
ISSN
 0009-9104 
Issue Date
2020-06
Keywords
CD20 ; Ca2+ ; STIM1 ; direct binding-induced cell death ; obinutuzumab ; raft
Abstract
Obinutuzumab is thought to exert its effects through its high antibody-dependent cellular cytotoxicity (ADCC) via glyco-engineering of the Fc region. In addition, obinutuzumab causes direct binding-induced cell death (DCD) only by specifically binding to its target CD20, a Ca2+ channel. However, the specific features of CD20 related to obinutuzumab binding-induction of cell death are not clearly understood. In this study, we evaluated the relationship between the Ca2+ channel features of CD20 as a store-operated Ca2+ channel (SOC) and obinutuzumab binding-induced cell death. Ca2+ channel function and biochemical analysis revealed that CD20 is an Orai1- and stromal interaction molecule (STIM1)-dependent Ca2+ pore. However, binding of obinutuzumab on CD20 did not have any effect on Ca2+ influx activity of CD20; the direct cell death rate mediated by obinutuzumab binding was almost equivalent with or without the extracellular Ca2+ condition. Given the apparent interaction between STIM1 and CD20, we observed Triton-X solubilized obinutuzumab-bound CD20 accompanied by STIM1. Subsequently, obinutuzumab binding and cell death were decreased by STIM1 knock-down in Ramos B cells. Thus, STIM1 directly contributes to cell death by increasing the affinity of cells for obinutuzumab by transferring CD20 to the Triton-soluble membrane region.
Full Text
https://onlinelibrary.wiley.com/doi/full/10.1111/cei.13427
DOI
10.1111/cei.13427
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Joo Young(김주영) ORCID logo https://orcid.org/0000-0003-2623-1491
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/179445
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