CD82 controls CpG-dependent TLR9 signaling

被引：22

作者：

Khan, Nida S. ^{[1
,2
,5
]}

Lukason, Daniel P. ^{[1
,4
]}

Feliu, Marianela ^{[1
]}

Ward, Rebecca A. ^{[1
]}

Lord, Allison K. ^{[1
]}

Reedy, Jennifer L. ^{[1
,5
]}

Ramirez-Ortiz, Zaida G. ^{[5
,6
,7
]}

Tam, Jenny M. ^{[1
]}

Kasperkovitz, Pia V. ^{[9
]}

Negoro, Paige E. ^{[1
]}

Vyas, Tammy D. ^{[1
]}

Xu, Shuying ^{[1
]}

Brinkmann, Melanie M. ^{[10
,11
]}

Acharaya, Mridu ^{[12
,13
]}

Artavanis-Tsakonas, Katerina ^{[14
]}

Frickel, Eva-Maria ^{[15
]}

Becker, Christine E. ^{[8
]}

Dagher, Zeina ^{[1
]}

Kim, You-Me ^{[16
]}

Latz, Eicke ^{[3
,17
,18
]}

Ploegh, Hidde L. ^{[19
]}

Mansour, Michael K. ^{[1
,5
]}

Miranti, Cindy K. ^{[20
,21
]}

Levitz, Stuart M. ^{[3
]}

Vyas, Jatin M. ^{[1
,5
]}

机构：

[1] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA

[2] Univ Massachusetts Med Sch, Biomed Engn & Biotechnol, Boston, MA USA

[3] Univ Massachusetts Med Sch, Dept Med, Boston, MA USA

[4] Univ Massachusetts, Biomed Engn & Biotechnol, Lowell, MA USA

[5] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA

[6] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02115 USA

[7] Harvard Med Sch, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA

[8] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02115 USA

[9] F Hoffmann La Roche Innovat Ctr Basel, Basel, Switzerland

[10] Helmholtz Ctr Infect Res, Viral Immune Modulat Res Grp, Braunschweig, Germany

[11] Tech Univ Carolo Wilhelmina Braunschweig, Inst Genet, Braunschweig, Germany

[12] Benaroya Res Inst, Seattle, WA USA

[13] Seattle Childrens Res Inst, Ctr Immun & Immunotherapy, Seattle, WA USA

[14] Univ Cambridge, Dept Pathol, Cambridge, England

[15] Francis Crick Inst, Host Toxoplasma Interact Lab, London, England

[16] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon, South Korea

[17] Univ Bonn, Univ Hosp Bonn, Inst Innate Immun, Bonn, Germany

[18] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany

[19] Boston Childrens Hosp, Boston, MA USA

[20] Van Andel Res Inst, Lab Integrin Signaling & Tumorigenesis, Grand Rapids, MI USA

[21] Univ Arizona, Canc Ctr, Dept Cellular & Mol Med, Tucson, AZ USA

来源：

FASEB JOURNAL | 2019年 / 33卷 / 11期

基金：

英国医学研究理事会; 英国惠康基金; 美国国家卫生研究院;

关键词：

tetraspanins; TLRs; myddosome; macrophages; RECEPTOR; 9; PROTEOLYTIC CLEAVAGE; ANTIGEN PRESENTATION; INNATE IMMUNITY; DECTIN-1; ACTIVATION; PROTEIN; TRAFFICKING; INDUCTION; PATHWAY;

D O I：

10.1096/fj.201901547R

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The tetraspanin CD82 is a potent suppressor of tumor metastasis and regulates several processes including signal transduction, cell adhesion, motility, and aggregation. However, the mechanisms by which CD82 participates in innate immunity are unknown. We report that CD82 is a key regulator of TLR9 trafficking and signaling. TLR9 recognizes unmethylated cytosine-phosphate-guanine (CpG) motifs present in viral, bacterial, and fungal DNA. We demonstrate that TLR9 and CD82 associate in macrophages, which occurs in the endoplasmic reticulum (ER) and post-ER. Moreover, CD82 is essential for TLR9-dependent myddosome formation in response to CpG stimulation. Finally, CD82 modulates TLR9-dependent NF-kappa B nuclear translocation, which is critical for inflammatory cytokine production. To our knowledge, this is the first time a tetraspanin has been implicated as a key regulator of TLR signaling. Collectively, our study demonstrates that CD82 is a specific regulator of TLR9 signaling, which may be critical in cancer immunotherapy approaches and coordinating the innate immune response to pathogens.

引用

页码：12500 / 12514

页数：15

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