Phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) by Src-family kinases (SFKs) is the first enzymatic step in the activation of an innate immune response during a pathogen encounter. Initiation of cell-activating signaling typically occurs within clusters of ITAM-coupled receptors such as FcγR (Guilliams et al., 2014) or the hemi-ITAM Dectin-1 (Brown, 2006; Deng et al., 2015), nucleated by highly multivalent immunoglobulin-G-decorated pathogens or fungal cell-wall β-glucans, respectively. Together, SFKs and phosphorylated ITAMs trigger activation of the tyrosine kinase Syk (Lowell, 2011). The SFKs and Syk then drive activation of membrane-proximal signaling through adaptor proteins; cytoskeleton-modulating proteins, such as the FAK/Pyk2 kinases and Paxillin; and Tec kinases, which activate second-messenger pathways via phosphoinositide 3-kinase (PI3K) and phospholipases Cγ (PLCγ1/2). These early events ultimately lead to downstream signaling through Erk1/2 and other pathways (Lowell, 2011). As the byproducts of activated macrophages can be toxic (e.g. release of reactive oxygen species) and drive inflammation (e.g. release of tumor necrosis factor α), the responsiveness of innate immune cells is tightly regulated (Goodridge et al., 2011; Takai, 2002; Sondermann, 2016; Chiffoleau, 2018).

Multiple mechanisms work together to tune the responsiveness of macrophages and other myeloid cells, including negative regulation by the phosphatases CD45 and CD148 (Goodridge et al., 2011; Freeman et al., 2016; Bakalar et al., 2018), cytoskeletal barriers to diffusion (Jaumouillé et al., 2014), signaling via immunoreceptor tyrosine inhibitory motifs (ITIMs) (Abram and Lowell, 2008) and inhibitory ITAMs (Hamerman and Lanier, 2006; Hamerman et al., 2009), and degradation and sequestration of signaling molecules targeted for polyubiquitination by ubiquitin ligases (Lutz-Nicoladoni et al., 2015; Liyasova et al., 2015). The SFKs, which in myeloid cells typically include Fgr, Fyn, two isoforms of Hck, and two splice forms of Lyn, may also have positive and negative functions (Abram and Lowell, 2008; Mkaddem et al., 2017; Alvarez-Errico et al., 2010; Scapini et al., 2009). Layered onto the traditional positive- and negative-regulatory roles of the SFKs, 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 (Freedman et al., 2015). This checkpoint can be bypassed when LynA is upregulated, with LynA acting as a rheostat to tune macrophage sensitivity. For instance, LynA is transcriptionally upregulated when macrophages are treated with interferon (IFN)-γ, and these primed cells have a lower threshold for SFK-mediated signaling (Freedman et al., 2015). The molecular mechanism that selectively targets LynA for polyubiquitination has not been elucidated previously.

Unlike Dectin-1 and FcγR signaling pathways in macrophages, which are typically triggered in the context of pathogen-induced µm-scale clusters of receptors (Goodridge et al., 2011; Freeman et al., 2016; Freedman et al., 2015), mast-cell FcεR signaling has a low threshold for activation; small or even monovalent antigen-IgE complexes can induce a signaling response in the context of a cell-particle interaction (Andrews et al., 2009; Felce et al., 2018; Carroll-Portillo et al., 2010). Supporting this more permissive signaling function, the binding dynamics of Syk with FcεRI in mast cells is unaffected by the size of receptor aggregates (Schwartz et al., 2017). Like macrophages, mast cells express LynA, and the disparity in the receptor sensitivity of these two cell types has not previously been explained.

This paper describes the mechanism by which activated LynA is selectively targeted for rapid degradation, thereby tuning both its steady-state expression and its activation kinetics 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 (Okuzumi et al., 2010; Okuzumi et al., 2009; Schoenborn et al., 2011), which specifically inhibits a variant of the SFK-inhibitory kinase Csk (Csk^AS) (Freedman et al., 2015; Schoenborn et al., 2011; Tan et al., 2014). Csk is responsible for phosphorylating a key inhibitory tyrosine in the C-terminal tail of all the SFKs. Inhibiting Csk^AS with 3-IB-PP1 disrupts the dynamic equilibrium between Csk and the phosphatases CD45 and CD148, which dephosphorylate the inhibitory tyrosine, leading to rapid and robust SFK activation (Chow and Veillette, 1995; Zhu et al., 2011). 3-IB-PP1-induced SFK activation leads to the phosphorylation and likely activation of the E3 ubiquitin ligase c-Cbl (Feshchenko et al., 1998; Dou et al., 2012; Freedman et al., 2015) and the preferential polyubiquitination and degradation of LynA in macrophages (Freedman et al., 2015), but it was not clear whether these two events were linked. Using knockout and overexpression models coupled with analyses of protein abundance and cell signaling, we now demonstrate that c-Cbl controls the steady-state expression of LynA and mediates its rapid degradation upon activation in macrophages. Quantitative targeted mass spectrometry shows that LynA is targeted by c-Cbl in response to phosphorylation of tyrosine 32 (Y32) within the LynA unique region, a process mediated by LynA, LynB or the shorter isoform of Hck. This recognition mode is distinct from the slower-phase action of c-Cbl and other E3 ligases on LynB and the other SFKs (Freedman et al., 2015; Sanjay et al., 2001; Sanjay et al., 2006). Finally, we have discovered that the LynA checkpoint is cell-specific. In mast cells, which express very little c-Cbl but abundant Cbl-b, LynA is not rapidly degraded upon activation, a function that can be rescued by induced overexpression of c-Cbl. The differential regulation of c-Cbl and LynA may drive mast cells toward a lower activation threshold than macrophages.

Polyubiquitination of signaling proteins by the Cbl family can lead to their degradation via the endolysosome or proteasome and to non-degradation-mediated inhibition (Duan et al., 2004). These E3 ligases must in turn be tightly regulated to prevent hyperresponsive or aberrant immune signaling while maintaining proper pathogen clearance (Zhu et al., 2016). Although highly homologous, c-Cbl and Cbl-b target different subsets of signaling proteins for inhibition and/or degradation (Thien and Langdon, 2005; Mohapatra et al., 2013), with c-Cbl polyubiquitinating the SFKs, including Lyn (Kyo et al., 2003; Shao et al., 2004), and Cbl-b acting on ITAM-coupled receptors, Syk, and other kinases (Purev et al., 2009; Sohn et al., 2003; Gustin et al., 2006; Zhu et al., 2016). c-Cbl binds via its phosphotyrosine-binding (PTB) domain to the SFK activation-loop phosphotyrosine (Sanjay et al., 2001) and via its PXXP motifs to the SFK SH3 domain (Sanjay et al., 2006). It is also an SFK substrate, requiring phosphorylation to become fully activated. These binding interfaces promote general c-Cbl interaction with all the SFKs. In this paper we report that c-Cbl targets LynA for rapid and specific degradation, a process that occurs with a half-life of a minute in BMDMs. In contrast, other E3 ligases contribute to the slower degradation mechanism shared among the other SFKs, including LynB, Fgr, Hck⁵⁹, Hck⁵⁶, Lck, FynB, and FynT, with the caveat that FynT does not seem to be activated in response to 3-IB-PP1.

c-Cbl is targeted to LynA via a noncanonical recognition site present in LynA but not the other SFKs. Although LynA and LynB have identical activation kinetics, lipidation sites, and activation-loop and SH3-domain sequences, LynA is degraded >10 fold more quickly than LynB in macrophages treated with the Csk^AS inhibitor/SFK activator 3-IB-PP1 (20). Exploiting the similarity between LynA and LynB to make a limited set of point mutations, we have discovered that, while activation-loop phosphorylation and SH3-domain interactions mediate slower-phase targeting by c-Cbl and other E3 ligases, rapid degradation of LynA is triggered by an interaction peculiar to its unique-domain insert region.

We have discovered that phosphorylation of Y32 in the unique-region insert of LynA is required for its rapid degradation. This phosphorylation occurs within seconds of LynA activation in macrophages, and flags LynA for rapid, c-Cbl-mediated polyubiquitination. Phosphorylation of LynA Y32 had been observed in neuroblastoma cell lines upon receptor-tyrosine-kinase activation (Palacios-Moreno et al., 2015). In epidermoid carcinoma (A431) cells and breast tumor samples LynA Y32 is phosphorylated by the epidermal growth factor receptor (EGFR), allowing it to phosphorylate MCM-7 and stimulate cell proliferation (Huang et al., 2013). We now present evidence that LynA Y32 is phosphorylated in primary macrophages, where this potentially positive-regulatory function paradoxically induces LynA to trigger its own c-Cbl-mediated polyubiquitination and degradation, a process underlying its function as a rheostat controlling the LynA checkpoint.

Kinase-impaired variants of LynA are not rapidly degraded, a result confirmed in macrophages treated with the SFK inhibitor PP2. Catalytically active LynA and LynB, however, can induce degradation of catalytically impaired LynA in trans. Interestingly, the shorter isoform of Hck can also induce degradation of LynA, although less efficiently than Lyn itself. Degradation of LynA depends on a minimum of two phosphorylation events: the phosphorylation of LynA Y32 and activating phosphorylation of c-Cbl (Feshchenko et al., 1998; Dou et al., 2012). The ability of individual Src family members to induce LynA degradation necessarily relies on the efficiency of these two processes. In cotransfection experiments, we found that some SFKs (FynB, Hck⁵⁹, Fgr, and Lck) were unable to induce degradation of kinase dead LynA^T410K despite an increase in their own activation-loop phosphorylation and their ability to phosphorylate the activation loop of LynA^T410K. This suggests, perhaps surprisingly (Lock et al., 1991; Carréno et al., 2000), that these kinases are not localized away from LynA or otherwise lacking in activity. Instead, it is likely that the induction of LynA degradation occurs via specific protein-protein interactions and/or substrate recognition interfaces. Unlike FynB and Hck⁵⁹, Fgr and Lck were able to phosphorylate c-Cbl, despite an earlier report that c-Cbl is a poor substrate for Lck and Zap70 (Feshchenko et al., 1998). On the other hand, Syk and FynT have both been reported to phosphorylate and activate c-Cbl (Feshchenko et al., 1998), but LynA degradation in 3-IB-PP1-treated BMDMs is unaffected by Syk inhibition and Fyn is not activated during 3-IB-PP1 treatment. Again, we conclude that the substrate preferences of the Src family members are tightly regulated, contradicting the assumption that downstream players in the ITAM signaling pathway are activated en bloc by semi-promiscuous kinases.

Rapid degradation of LynA is easily observed upon bulk SFK activation by 3-IB-PP1 but also affects the steady-state level of LynA protein, likely due to the selective degradation of small amounts (Freedman et al., 2015) of basally active LynA over time. Although the unique region of LynA lacks a c-Cbl consensus recognition motif (Thien and Langdon, 2005), pY32 could serve as a docking site for the PTB domain of c-Cbl. In this ultrafast feedback process, activation-loop- and Y32-autophosphorylated LynA could efficiently phosphorylate and activate c-Cbl and trigger its own degradation, potentially then releasing c-Cbl for other positive- and negative-regulatory signaling functions. Earlier work has shown that although the interactome of transfected LynA^Y32F in mammary adenocarcinoma (MDA-MB-231) cells more closely resembles that of wild-type LynA than LynB, some LynA interactions are lost (Tornillo et al., 2018). It is also possible that, by analogy to a similarly situated but non-homologous phosphorylation site in Hck (pY29) (Johnson et al., 2000), phosphorylation of LynA Y32 could be directly activating. The unique regions of LynA and LynB make distinct SH3-domain contacts (Teixeira et al., 2018), and phosphorylation could alter these interactions and increase kinase activity. Hyperactivated LynA could then efficiently phosphorylate and activate nearby or pre-complexed c-Cbl, triggering its own degradation more aggressively than do the other SFKs.

LynA and LynB have been reported to interact with different subsets of proteins in mast cells and in triple-negative breast cancer cells, with LynA signaling via ITAM (Alvarez-Errico et al., 2010), cytoskeletal, and proliferative (Tornillo et al., 2018) pathways and LynB initiating negative feedback via ITIMs and phosphatases (Alvarez-Errico et al., 2010). In mammary epithelial cells the ratio of LynA and LynB is actively regulated by Epithelial Splicing Regulatory Protein 1 (ESRP1). LynA-upregulated tumors have the more invasive phenotype (Tornillo et al., 2018). The positive-regulatory roles reported for LynA in mast and tumor cells complements our own observations that LynA degradation can block macrophage signaling through the Erk1/2, Akt, and NFAT pathways, which cannot be rescued by active LynB (Freedman et al., 2015).

Aberrant activation driven by ITAM signaling pathways in macrophages is a known driver of autoimmune and inflammatory disease, with activated macrophages accumulating in chronically inflamed tissues in the absence of an active infection (Wynn et al., 2013). Regulation of LynA protein expression and deactivation kinetics by c-Cbl could, via the LynA checkpoint, prevent the initiation of pathological signaling. The threshold for macrophage activation is modulated by changes to their local environment. For example, IFN-γ and LPS polarize macrophages for a pro-inflammatory response, whereas IL-4 and IL-13 polarize macrophages for tissue repair (i.e. collagen deposition) and inflammatory resolution (Galli et al., 2011; Bosurgi et al., 2017). We have reported that IFN-γ decreases the macrophage signaling threshold in part by increasing the expression of LynA (Freedman et al., 2015). Dynamic changes in SFK and c-Cbl levels could modulate the macrophage activation threshold, ensuring that macrophages respond appropriately during times of infection (low threshold) and limiting aberrant activation in response to cellular debris and small-scale antibody complexes during inflammatory resolution (high threshold).

Like macrophages, mast cells reside in nearly every tissue and perform environment-specific functions in addition to sensing non-self (Galli et al., 2011; Gentek et al., 2018). While macrophages have distinct anti-inflammatory roles as professional phagocytes in the silent clearance of apoptotic cells and agents of wound healing, mast cells are constitutively primed for ITAM-induced triggering, releasing preformed granules that contain inflammatory cytokines, chemokines, prostaglandins, and proteases. Pursuant to these differing functions, macrophages continuously gauge ITAM ligand valency (i.e. particle size) and have a relatively high basal threshold for inflammatory activation (Goodridge et al., 2011; Freedman et al., 2015), while mast cells can be triggered by small-scale receptor clustering induced by low-valency or even monovalent FcεR-IgE-allergen complexes (Andrews et al., 2009; Felce et al., 2018). One striking difference between the macrophage and mast-cell ITAM regulatory machinery is that mast cells express almost no c-Cbl. In spite of low reported mRNA levels (ImmGen; Heng and Painter, 2008; Dwyer et al., 2016), mast cells constitutively express a high level of LynA protein, likely due to impaired steady-state degradation of basally active LynA. Furthermore, LynA is not degraded upon activation and 3-IB-PP1 triggers a stronger Erk phosphorylation response in the absence of ITAM-receptor ligation in mast cells than in rested macrophages.

In summary, we describe a model in which regulation of LynA and c-Cbl levels helps to determine an immune cell’s potential for inflammatory ITAM signaling. Regulated degradation tunes down the LynA rheostat, blocking cell signaling via the LynA checkpoint at low cellular doses of LynA and overriding the LynA checkpoint at higher doses. In macrophages this occurs on a continuum where LynA dose is highest in cells rendered more reactive by IFN-γ priming (polarization). Mast cells express almost no c-Cbl and maintain high levels of LynA at steady state and over time, consistent with permissive signaling in the absence of a large-scale ITAM receptor clustering event nucleated by multivalent receptor ligation. Appropriate regulation of immune receptor thresholds is critical for maintaining the function of innate immune cells; threshold dysregulation can lead to chronic feedback loops that drive inflammatory signaling in autoimmune disease and conversely tumor-supporting immunosuppressive signaling (Wynn et al., 2013). Elucidating the mechanisms by which the LynA checkpoint is regulated may allow us to tune immune-cell sensitivity and reprogram pathological cells.

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for graphs in Figure 1, Figure 1-figure supplement 1, Figure 2, Figure 3, Figure 3-figure supplement 2, Figure 4, Figure 4-figure supplement 1, Figure 4-figure supplement 5, Figure 5, Figure 6, Figure 6-figure supplement 1, Figure 7, Figure 8, and Figure 9. Data sets and calibration curves resulting from our targeted mass spectrometry studies have been deposited in Panorama Public (https://panoramaweb.org/project/Panorama%20Public/begin.view?).

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Author details

1. Ben F Brian IV

   Department of Pharmacology, University of Minnesota, Minneapolis, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

2. Adrienne S Jolicoeur

   Department of Pharmacology, University of Minnesota, Minneapolis, United States

   Contribution

   Formal analysis, Validation, Investigation, Visualization, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

3. Candace R Guerrero

   College of Biological Sciences Center for Mass Spectrometry and Proteomics, University of Minnesota, Minneapolis, United States

   Contribution

   Formal analysis, Validation, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

4. Myra G Nunez

   Department of Pharmacology, University of Minnesota, Minneapolis, United States

   Contribution

   Formal analysis, Validation, Investigation, Visualization, Writing—review and editing

   Competing interests

   No competing interests declared

5. Zoi E Sychev

   Department of Pharmacology, University of Minnesota, Minneapolis, United States

   Contribution

   Formal analysis, Validation, Investigation, Visualization, Writing—review and editing

   Competing interests

   No competing interests declared

6. Siv A Hegre

   Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

   Contribution

   Formal analysis, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

7. Pål Sætrom

   1. Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
   2. Department of Computer Science, Norwegian University of Science and Technology, Trondheim, Norway

   Contribution

   Formal analysis, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8142-7441

8. Nagy Habib

   Department of Surgery and Cancer, Hammersmith Hospital, Imperial College London, London, United Kingdom

   Contribution

   Formal analysis, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4920-4154

9. Justin M Drake

   1. Department of Pharmacology, University of Minnesota, Minneapolis, United States
   2. Masonic Cancer Center, University of Minnesota, Minneapolis, United States
   3. Department of Urology, University of Minnesota, Minneapolis, United States

   Contribution

   Formal analysis, Supervision, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

10. Kathryn L Schwertfeger

    1. Department of Pharmacology, University of Minnesota, Minneapolis, United States
    2. Masonic Cancer Center, University of Minnesota, Minneapolis, United States
    3. Center for Immunology, University of Minnesota, Minneapolis, United States
    4. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, United States

    Contribution

    Formal analysis, Supervision, Funding acquisition, Project administration, Writing—review and editing

    Competing interests

    No competing interests declared

11. Tanya S Freedman

    1. Department of Pharmacology, University of Minnesota, Minneapolis, United States
    2. Masonic Cancer Center, University of Minnesota, Minneapolis, United States
    3. Center for Immunology, University of Minnesota, Minneapolis, United States
    4. Center for Autoimmune Diseases Research, University of Minnesota, Minneapolis, United States

    Contribution

    Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

    For correspondence

    tfreedma@umn.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5168-5829

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