Type

Journal Article

Authors

Caroline A Jefferies
Warren Thomas
Eoghan McCarthy
Barbara M Coffey
Kevin B Stacey
Joan Ní Gabhann
Jennifer C Byrne

Subjects

Biochemistry

Topics
metabolism protein tyrosine kinases complement c1q lrp1 protein mouse myeloid cells immunology macrophages agammaglobulinaemia tyrosine kinase genetics toll like receptor 7 signal transduction phagocytosis lymphocyte activation phosphorylation animals receptors ldl tlr7 protein mouse apoptosis antibodies blocking cell membrane membrane proteins tumor suppressor proteins calreticulin cell line membrane glycoproteins mice

Bruton's tyrosine kinase is required for apoptotic cell uptake via regulating the phosphorylation and localization of calreticulin. (2013)

Abstract In addition to regulating B cell development and activation, Bruton's tyrosine kinase (Btk) functions downstream of multiple TLRs, including TLR7, to regulate innate immune responses in myeloid cells. Although critical for defense against RNA viruses such as influenza and Sendai virus, recognition of self-RNA by TLR7 also has been shown to be an important contributor to the pathophysiology of systemic lupus erythematosus. To date, the role of Btk in regulating TLR7-mediated responses is poorly understood. In the current study, we have demonstrated a hitherto undiscovered role for Btk in apoptotic cell uptake, identifying the molecular chaperone calreticulin (CRT) as a novel substrate for Btk in regulating this response. CRT together with the transmembrane receptor CD91 function at the cell membrane and regulate uptake of C1q-opsonised apoptotic cells. Our results show that Btk directly phosphorylates CRT and that in the absence of Btk, CRT fails to localize with CD91 at the cell surface and at the phagocytic cup. Critically, a blocking Ab against CRT in wild-type macrophages mimics the inability of Btk-deficient macrophages to phagocytose apoptotic cells efficiently, indicating the critical importance of Btk in regulating CRT-driven apoptotic cell uptake. Our data have revealed a novel regulatory role for Btk in mediating apoptotic cell clearance, with CRT identified as the critical component of the CRT/CD91/C1q system targeted by Btk. Given the importance of clearing apoptotic cell debris to prevent inappropriate exposure of TLRs to endogenous ligands, our results have important implications regarding the role of Btk in myeloid cell function.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Caroline A Jefferies, Warren Thomas, Eoghan McCarthy, Barbara M Coffey, Kevin B Stacey, Joan Ní Gabhann, Jennifer C Byrne

Experts in our system

1
Caroline A Jefferies
Royal College of Surgeons in Ireland
Total Publications: 50
 
2
Warren Thomas
Royal College of Surgeons in Ireland
Total Publications: 48
 
3
Eoghan McCarthy
Royal College of Surgeons in Ireland
Total Publications: 19
 
4
Joan Ní Gabhann
Royal College of Surgeons in Ireland
Total Publications: 23