| SCGF is a novel innate immune protector against infection. SARS-CoV-2-infected patients with higher serum SCGF level are asymptomatic (632). The finding indicates that serum SCGF level determines onset of SARS-CoV-2 infection, and more importantly, SCGF could control a novel protective innate immune mechanisms against infection, for example by binding to SARS-CoV-2 spike protein to protect ACE2+ cells from viral invasion. Alternatively SCGF competes with SARS-CoV-2 spike protein through RGD peptide for binding to integrinα5β1 of target cells and resultantly inhibits viral invasion into cells (667,668). As for 2018-2019 outbreak of Andes orthohantavirus pulmonary syndrome in Argentina, reduced serum SCGF level is associated with hantavirus spreaders compared to non-spreaders, and among spreaders, notably with superspreaders compared to non-superspreaders (636). Like SARS-CoV-2 infection SCGF could be a critical player of innate immunity against hantavirus infection. Scgf gene expression is up-regulatedin vitro in rainbow trout head kidney cells in response to fungal PAMPs including β-glucan peptide and furfurman (663). SCGF could exhibit innate immunity against fungus infection, e.g. Malassezia furfur, like same C-type lectin dectin-2 that is a receptor for furfurman. NF-κB regulates scgf positively or negatively? Gene network plays a key role in cell proliferation. As forscgf, an interaction with NF-κB is important but results in diverse and complex effects depending on cell types and experimental design. Overexpression and/or knockdown of each or both of scgf and NF-κB clarify the interaction-induced effects in a variety of cells. SCGF interactome: Sav1, Cep85, Traf2/7, XIAP Protein-protein interaction database BioGRID3.5presents a list of SCGF-interacting proteins. They are demonstrated using affinity purification mass spectrometry of HA-tagged SCGF expressed in HEK293T cells. In particular, several proteins below play a crucial role in malignancy, cell proliferation and apoptosis. Sav1 (Salvador homolog 1) interacts with Mst1/2 to activate LATS1/2 and inhibits YAP/TAZ-TEAD1-4 pathway in Hippo signal transduction to suppress cell proliferation. Liver-specific sav1knockout induces hepatocellular carcinoma (HCC) in nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) model mice (591). SCGF binds to SAV1 to unleash the SAV1-induced inhibition in Hippo pathway resulting in HCC progression. SCGF-SAV1 mediated mechanism in HCC promotion is consistent with the clinical finding that scgf is a poor prognostic signature gene in HCC (587). Anti-scgf therapy is rational for anti-HCC therapy. Cep85 is located in centrosome but little characterized. SCGF is immunohistochemically detected in centrosome (The Human Protein Atlas), indicating that SCGF-Cep85 interaction in centrosome fulfills some function in cell division. Traf2/7 and XIAP are major apoptotic proteins. SCGF is predicted to block apoptosis by an interaction with them. SCGF-induced inhibition of apoptosis favorably accelerates malignant cell growth. Anti-scgf therapy contributes to eradicate scgf-upregulated malignancies, and SCGF is reasonably administered to treat scgf-downregulated diseases, e.g. aplastic anemia. SCGF Receptor (SCGFR) SCGFR is unidentified yet. SCGFR is predictedly expressed on stem cells themselves, and minority of stem cell population in the normal tissues makes it difficult to recover SCGFR+cells enough to analyze SCGF- SCGFR interaction and identify SCGFR gene. A possible candidate for identifying SCGFR seems to be malignant cell lines of leukemia or cancer origin, particularly their Hoechst 33342-excluding side population can be promising. Identification of SCGFR is a prerequisite for analyzing proliferation mechanisms of stem cells, even if SCGF takes a part in making physiologically quiescent stem cells enter into the cell cycle in response to certain stimuli. SCGFR, if identified, could provide more important proliferation mechanisms of normal and cancer stem cells and further enable regulating an SCGF-SCGFR interaction to treat cancer. What function does exosomal SCGF carry out? Is SCGF a transcriptokine bifunctioning as cytokine and intracellular regulator? SCGF is extracellularly secreted or released into exosomes/microvesicles from a variety of cells including MSCs, normal and cancer cells, and acts on the ambient and remote cells. SCGF also possibly remains intracellularly. SCGF binds to SCGFR and/or integrin, is incorporated along microtubules by the guidance of elevator proteins or through exosomes, and carries out some function in the cytoplasm and intracellular organelles, e.g. centrosome. SCGF can be a protein bifunctioning as cytokine (SCGFR- and/or integrin- mediated signal transduction) and intracellular regulator (transcription factor and protein-protein interaction) for cell division and proliferation SCGF, a therapeutic target for cancer and leukemia cells Apoptosis is induced in cancer cells through SCGF exhaustion using anti-SCGF antibody or scgf siRNA. SCGF is a potential therapeutic target for cancer and leukemia cells including their stem cells. What type of sugar does SCGF bind? Sugar target for SCGF has not yet been identified. Tetranectin, C-type lectin roughly akin to SCGF, does not bind to sugar, implicating that SCGF does not bind to any specific sugar although it has a C-type lectin structure. |