Dysregulation of Protein S in COVID-19.

Coronavirus Disease 2019 (COVID-19) has been widely associated with increased thrombotic risk, with many different proposed mechanisms. One such mechanism is acquired deficiency of protein S (PS), a plasma protein that regulates coagulation and inflammatory processes, including complement activation and efferocytosis. Acquired PS deficiency is common in patients with severe viral infections and has been reported in multiple studies of COVID-19. This deficiency may be caused by consumption, degradation, or clearance of the protein, by decreased synthesis, or by binding of PS to other plasma proteins, which block its anticoagulant activity. Here, we review the functions of PS, the evidence of acquired PS deficiency in COVID-19 patients, the potential mechanisms of PS deficiency, and the evidence that those mechanisms may be occurring in COVID-19.

Gas6/TAM Axis Involvement in Modulating Inflammation and Fibrosis in COVID-19 Patients.

Gas6 (growth arrest-specific gene 6) is a widely expressed vitamin K-dependent protein that is involved in many biological processes such as homeostatic regulation, inflammation and repair/fibrotic processes. It is known that it is the main ligand of TAMs, a tyrosine kinase receptor family of three members, namely MerTK, Tyro-3 and Axl, for which it displays the highest affinity. Gas6/TAM axis activation is known to be involved in modulating inflammatory responses as well as fibrotic evolution in many different pathological conditions. Due to the rapidly evolving COVID-19 pandemic, this review will focus on Gas6/TAM axis activation in SARS-CoV-2 infection, where de-regulated inflammatory responses and fibrosis represent a relevant feature of severe disease manifestation. Furthermore, this review will highlight the most recent scientific evidence supporting an unsuspected role of Axl as a SARS-CoV-2 infection driver, and the potential therapeutic advantages of the use of existing Axl inhibitors in COVID-19 management. From a physiological point of view, the Gas6/TAM axis plays a dual role, fostering the tissue repair processes or leading to organ damage and loss of function, depending on the prevalence of its anti-inflammatory or profibrotic properties. This review makes a strong case for further research focusing on the Gas6/TAM axis as a pharmacological target to manage different disease conditions, such as chronic fibrosis or COVID-19.

Endocytic trafficking of GAS6-AXL complexes is associated with sustained AKT activation.

AXL, a TAM receptor tyrosine kinase (RTK), and its ligand growth arrest-specific 6 (GAS6) are implicated in cancer metastasis and drug resistance, and cellular entry of viruses. Given this, AXL is an attractive therapeutic target, and its inhibitors are being tested in cancer and COVID-19 clinical trials. Still, astonishingly little is known about intracellular mechanisms that control its function. Here, we characterized endocytosis of AXL, a process known to regulate intracellular functions of RTKs. Consistent with the notion that AXL is a primary receptor for GAS6, its depletion was sufficient to block GAS6 internalization. We discovered that upon receptor ligation, GAS6-AXL complexes were rapidly internalized via several endocytic pathways including both clathrin-mediated and clathrin-independent routes, among the latter the CLIC/GEEC pathway and macropinocytosis. The internalization of AXL was strictly dependent on its kinase activity. In comparison to other RTKs, AXL was endocytosed faster and the majority of the internalized receptor was not degraded but rather recycled via SNX1-positive endosomes. This trafficking pattern coincided with sustained AKT activation upon GAS6 stimulation. Specifically, reduced internalization of GAS6-AXL upon the CLIC/GEEC downregulation intensified, whereas impaired recycling due to depletion of SNX1 and SNX2 attenuated AKT signaling. Altogether, our data uncover the coupling between AXL endocytic trafficking and AKT signaling upon GAS6 stimulation. Moreover, our study provides a rationale for pharmacological inhibition of AXL in antiviral therapy as viruses utilize GAS6-AXL-triggered endocytosis to enter cells.