Biology subjects

Senevirathne, S. E.

Publications and source records attributed to Senevirathne, S. E..

3 recordsLinked to original sources

bioRxiv2026

Dose-dependent activation of Syk and SHIP1 by LynA and LynB at steady state creates a threshold for macrophage signaling in the absence of receptor engagement

LynA-knockout and LynB-knockout mice, each expressing only one of two isoforms of the Src-family kinase (SFK) Lyn, have differential progression to autoimmunity. It is unclear, however, whether isoform-specificity or Lyn dose underlies differential signaling in the single-isoform knockouts. To address this question, we generated a series of Lyn-knockout mice with a varying LynA and LynB expression and tested macrophage signaling in response to pharmacological pan-SFK activation. We found that the magnitude of initiating signaling is a function of the combined basal expression of LynA and LynB, with the two isoforms equally capable of phosphorylating positive-regulatory Syk and negative-regulatory SHIP1. While expression of either isoform restored basal and SFK-initiated downstream signaling, WT-like levels of Erk and Akt signaling were enabled by expression of any amount of Lyn and insensitive to further upregulation of either isoform. Thus, either LynA or LynB expression at steady state leads to balanced activation of positive- and negative-regulatory signaling, setting a maximal response in the absence of a true microbial encounter. Summary SentenceTotal expression of LynA and LynB determines the steady-state phosphorylation of the activating kinase Syk and the inhibitory phosphatase SHIP1, capping signaling in the absence of a microbial encounter.

immunology↗

bioRxiv2025

Steady-state phosphorylation of SHIP1 by Lyn restricts macrophage activation in the absence of a phagocytic synapse

Microscale engagement of the hemi-ITAM-containing receptor Dectin-1 by a fungus-derived particle initiates signaling through the Src-family kinases (SFKs) and Syk that leads to downstream Erk and Akt activation and the macrophage anti-microbial response. To minimize local tissue damage in the absence of a true pathogenic threat, macrophages must remain unresponsive to low-valency receptor ligation by soluble ligands from food or remote infection sites. To investigate how SFKs regulate macrophage sensitivity, we compared signaling in murine bone-marrow-derived macrophages (BMDMs) exposed to depleted zymosan, a particulate and highly multivalent Dectin-1 ligand, with signaling after pharmacologically induced SFK activation without receptor engagement or formation of a phagocytic synapse. We show that high-valency Dectin-1 engagement and formation of a phagocytic synapse restrict phosphorylation of the ITIM-associated phosphatase SHIP1 and promote Erk and Akt signaling. In contrast, SFK activation in the absence of a phagocytic synapse induces phosphorylation of SHIP1 and leads to dampened activation of Erk and Akt. Whereas multiple SFKs are capable of phos-phorylating SHIP1 in principle, the SFK Lyn functions uniquely in maintaining steady-state phosphorylation of SHIP1 and setting tonic and induced levels of Erk and Akt phosphorylation. Consequently, Lyn has a special role in suppressing the Akt pathway and maintaining Erk/Akt pathway balance. Interestingly, formation of a phagocytic synapse circumvents this requirement for Lyn to maintain Erk/Akt balance. These findings highlight the unique function of Lyn in maintaining mac-rophage steady-state signaling and limiting pro-inflammatory responses to disorganized pathway activation and soluble microbial components.

immunology↗

bioRxiv2021

Splice-specific lyn knockout mice reveal a dominant function of LynB in preventing autoimmunity

The unique roles of the Src-family kinases LynA and LynB in immune activating and inhibitory signaling have eluded definition. Here we report that LynB, the shorter splice product of lyn, carries the dominant immunosuppressive function. We used CRISPR/Cas9 gene editing to constrain lyn splicing and expression to a single product: LynAKO or LynBKO mice. While activities of both isoforms regulate homeostatic Lyn expression, only LynB protects against autoimmune disease. LynBKO monocytes and dendritic cells are TLR4-hyper-responsive, and TLR4 expression increases with age in LynBKO myeloid and B cells. These changes are accompanied by the development of an inflammatory disease that resembles human systemic lupus erythematosus (SLE). The interplay between LynB and TLR4 likely underlies the autoimmunity risk associated with LYN hypomorph and TLR4 hypermorph alleles.

immunology↗