LynA regulates an inflammation-sensitive signaling checkpoint in macrophages

Abstract

Clustering of receptors associated with immunoreceptor tyrosine-based activation motifs (ITAMs) initiates the macrophage antimicrobial response. ITAM receptors engage Src-family tyrosine kinases (SFKs) to initiate phagocytosis and macrophage activation. Macrophages also encounter nonpathogenic molecules that cluster receptors weakly and must tune their sensitivity to avoid inappropriate responses. To investigate this response threshold, we compared signaling in the presence and absence of receptor clustering using a small-molecule inhibitor of Csk, which increased SFK activation and produced robust membrane-proximal signaling. Surprisingly, receptor-independent SFK activation led to a downstream signaling blockade associated with rapid degradation of the SFK LynA. Inflammatory priming of macrophages upregulated LynA and promoted receptor-independent signaling. In contrast, clustering the hemi-ITAM receptor Dectin-1 induced signaling that did not require LynA or inflammatory priming. Together, the basal-state signaling checkpoint regulated by LynA expression and degradation and the signaling reorganization initiated by receptor clustering allow cells to discriminate optimally between pathogens and nonpathogens.DOI: http://dx.doi.org/10.7554/eLife.09183.001

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

“…1C and Supplemental Fig. S4A), as previous reports indicate, showing the early activation of SFK, including LYN, in macrophages and B cells (26,27). On the other hand, LYN activity was gradually decreased for the duration of over 12 h after oAb 1-42 exposure (Fig.…”

The immune cell landscape in kidneys of lupus nephritis patients

“…6b-g). We found that CSK and LYN, which regulate the Src family kinase response to weak signals and act as a rheostat for inflammatory signaling 39 are downregulated along this trajectory, making the macrophages less inflammatory as they transition. A concurrent upregulation of CIITA and HLA-DQA1 suggests an increasing role in antigen presentation.…”

An orthogonal c-Cbl recognition mode targets LynA for rapid degradation and builds specificity into the LynA checkpoint

“…The SFKs, which in myeloid cells typically include Fgr, Fyn, and two splice forms each of Hck and Lyn, may also have positive and negative functions (12, 17–19). Layered onto the traditional positive-and negative-regulatory roles of the SFKs, we have shown that activated LynA (the longer of the two Lyn splice forms) is rapidly and specifically targeted for polyubiquitination and degradation, forming the basis of a signaling checkpoint that blocks spurious macrophage activation (20). The mechanism preferentially targeting LynA for polyubiquitination and the molecular basis of this selectivity have not been elucidated previously.…”

“…Unlike Dectin-1 and FcγR signaling in macrophages, which is typically triggered in the context of pathogen-induced µm-scale clusters of receptors (5, 9, 20), mast-cell FcεR signaling has a low threshold for activation--small or even monovalent antigen-IgE complexes are sufficient to induce a signaling response (21, 22). Like macrophages, mast cells express LynA, and this disparity in receptor sensitivity has not previously been explained.…”

“…This paper describes the mechanism by which active LynA is selectively recognized and rapidly degraded, tuning its activation kinetics and its steady-state protein levels in a cell-specific manner. To reveal the requirements for LynA degradation, we synchronized receptor-independent SFK activation using the designer inhibitor 3-IB-PP1 (23–25), which specifically inhibits a variant of the SFK-inhibitory kinase Csk (Csk AS ) (20, 25, 26). Csk is responsible for phosphorylating a key inhibitory tyrosine in the C-terminus of all the SFKs.…”