Browsing by Subject "toll-like receptor"

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    Regulation of the kinases LynA and LynB and function in autoimmune disease
    (2021-04) Brian, Ben
    Cell-surface receptors on immune cells direct immune-cell function by sensing and responding to signs of pathogens and tissue damage. Signaling initiated by immunoreceptors is responsible for essential aspects of the immune response, including phagocytosis by myeloid cells, and antigen sensing by B and T cells. Efficient regulation of immunoreceptor signaling ensures that inflammation arising from pathogen clearance is limited in order to prevent tissue damage. Autoimmune diseases, such as systemic lupus erythematosus, can occur when these signaling pathways are improperly regulated. The tyrosine kinase Lyn is an important regulator of immune function due to its unique ability to both initiate signaling that can generate inflammation, and also recruit and activate proteins that dampen cellular activation. Alterations to Lyn expression and signaling in both human and mice can worsen or cause autoimmune disease. Understanding how Lyn is regulated and balances these roles is necessary to develop therapies that selectively limit autoinflammation but preserve pathogen clearance. Alternative splicing of the lyn gene produces two proteins, LynA and LynB, that differ by the presence of a 21-amino-acid insert present in LynA and absent in LynB. Here, we demonstrate the LynA and LynB are differentially regulated in immune cells. Phosphorylation of LynA at Tyrosine 32 in its unique region causes LynA to be rapidly, and selectively, poly-ubiquitinated by an E3 ligase, c-Cbl, and degraded. We show that differential expression of c-Cbl in macrophages and mast cells controls LynA protein levels, degradation, and signaling responses following Src-family kinase activation. Furthermore, we created novel knockout mice to study the roles LynA and LynB play in regulating autoimmune disease. Using these novel mice, we show that LynB prevents the development of splenomegaly and autoimmunity by limiting myeloid cell expansion and B cell activation. We also demonstrate that LynB-deficient mice have elevated responses to Toll-like receptor activation. Together, these results indicate that LynA and LynB are differentially regulated and have unique roles in the immune response. Therefore, understanding LynA and LynB signaling and regulation could yield targets that limit inflammation but preserve normal immune function.