Functions of SURF4 gene in vivo

To the Editor: Recently, we reviewed almost all the articles reporting surfeit locus containing the six sequence-unrelated housekeeping genes Surfeit 1 to Surfeit 6 since 1988 and one of the family members, surfeit 4 (SURF 4) gene interested us. In this article, we will summarize the characteristics and protein localization of SURF4 gene, as well as its possible physiological functions and pathogenesis in various diseases and cancers, expecting to explore its clinical application values. The human surfeit locus was located in chromosome band 9q34.[1] Human SURF4 was first described by Reeves and Fried[2] in 1995 as a multi-transmembrane protein with a molecular weight of 30 000. It had heterogeneous transcription start sites with shorter introns and exons. Its 5′ end was located on cytosine-phosphoric acid-guanine (CpG)-rich islands (the promoter of a housekeeping genes), and its messenger ribonucleic acid (mRNA) was widely expressed in the cells of various organisms. Its carboxyl terminal had double lysine endoplasmic reticulum (ER) retrieval motifs, and its gene encoded a membrane protein associated with the ER. SURF4 might be considered as a transmembrane protein, located at the ER-Golgi intermediate compartment (ERGIC) and ER, and a circulating protein in the early secretion pathway.[3] SURF4 was previously thought to be one of housekeeping genes, whose expression level would remain stable and would not vary by tissue types, cell development stages, cell cycle states, external signals, treatments, or abnormal disease status.[4] In recent years, SURF4 has been reported to be downregulated in undifferentiated teratocarcinoma cells, and has an effect on human malignancies. In brain and breast cancers, lymphoma and myeloma, the expression of SURF4 was found to increase significantly, and the median overall survival of patients with high SURF4 expression was significantly shorter than those with low SURF4 expression. An experimental study found that mouse embryonic fibroblast cell line established at the NIH3T3 cells (mouse embryonic fibroblast cell line established at the National Institutes of Health) that overexpressed SURF4 induced anchorage-independent growth and transformation of cells in vitro, and tumor growth in vivo in mice.[5] Yue et al[6] demonstrated that SURF4 was up-regulated in ovarian cancer stem cells (OCSCs). Down-regulation of SURF4 could reduce the expression of the transcription factor SOX2 and the proto-oncogene C-MYC in OCSCs, inhibit tumor self-renewal ability, and improve the sensitivity of OCSCs to chemotherapy drugs. Hence, we hypothesize that SURF4 modulates cellular functions and is important for oncogenic transformation in vivo. It may play a carcinogenic role in the occurrence of tumors, and its expression is related to the tumor invasion and clinical outcomes of cancer patients. However, none of the articles explained why SURF4 would show these changes in tumors, so we need to carry out more studies in the future. As a cargo receptor, SURF4 protein interacts with the amino terminal tripeptides exposed after the removal of the leader sequences to establish different steady-state concentrations of a variety of soluble cargo proteins in the ER. Human cells lacking SURF4 will no longer preferentially traffick cargo expressing strong ER exit by soluble cargo using amino-terminal peptide-encoding motif (ER-ESCAPE motif). When SURF4 is re-expressed, the enhanced ER transport in SURF4-deficient cells is rescued, and the soluble substances in ER is preferentially output to maintain the protein below the concentration of becoming harmful aggregates.[7,8] Saegusa et al[8] proved that the loss of sft-4 (a caenorhabditis elegans homologue of SURF4) led to the accumulation of apolipoprotein B (Apo B) in human hepatic cells, and the deletion of sft-4 reduced the number of coat protein complex II (COPII)-positive ER exit sites. SURF4 is a promising new target for the identification and treatment of dyslipidemia, including Anderson's disease/chylomicron (CM) retention disease (AD/CMRD) and hyperlipidemia.[8,9] Deletion of SURF4 resulted in ER accumulation and reduced extracellular secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9), which would lead to hypercholesterolemia. These findings support SURF4 as a model of ER cargo receptor mediating efficient secretion of PCSK9 and suggest that SURF4 may be a new therapeutic target for hypercholesterolemia.[10,11] Emmer et al[12] found the appearance, behavior, body weight, fecundity, and organ development of heterozygous surf4 mice were generally normal, with no significant changes in circulating plasma levels of PCSK9, Apo B, total cholesterol, or hepatic accumulation of Apo B. However, homozygous surf4 mice showed embryonic lethality, with all surf4 offspring which died between embryonic days 3.5 and 9.5. The embryonic lethality of homozygous surf4 mice implies the existence of additional surf4 cargoes or functions that are critical for early embryonic development. As a Ca2+-binding membrane protein localized in the ER, stromal interacting molecule 1 (STIM1) is a sensor of Ca2+ and a critical activator of Ca2+ release-activated Ca2+ (CRAC). When Ca2+ concentration was low, STIM1 was activated and interacted with CRAC to promote store-operated Ca2+ entry (SOCE). When Ca2+ concentration returned to normal, STIM1 dissociated from CRAC protein to prevent SOCE and returned to an inactive state. Studies suggested that STIM1 was related to SURF4, and the luminal region of the ER participated in the interaction between STIM1 and SURF4, in which SURF4 was the binding partner of STIM1. The interaction between SURF4 and STIM1 reduced the aggregation of STIM1 and SOCE.[13]SURF4 negatively regulates STIM1-mediated SOCE. Lin et al[14] demonstrated that the loss of SURF4 resulted in the accumulation of erythropoietin (EPO) in the ER and defective endogenous EPO secretion, and over-expression of SURF4 led to increased EPO secretion, which suggested that SURF4 may be an effective treatment target for disorders of erythropoiesis driven by abnormal EPO levels. Xangsayarath et al[15] concluded that the Plasmodium falciparum surf 4.1 was highly polymorphic and therefore a potential candidate for vaccine development by evaluating the polymorphism, positive selection, linkage disequilibrium, and temporal changes in the frequency distribution of surf 4.1 gene sequence. Kong et al[16] found that surf4 is a novel cofactor involved in the replication of positive-strand RNA viruses with double-membrane vesicles (DMVs) as the RNA replication sites, such as hepatitis C virus. These findings provide potential new targets for preventing the formation of DMVs during viral replication and for the diagnosis and treatment of positive-strand RNA viruses. Atay et al[17] conducted high-quality proteomic studies on gastrointestinal stromal tumor-derived exosomes (GDEs) with high quality and showed that SURF4 protein was one of the proteins associated with imatinib mesylate reaction in both in vitro- and in vivo-derived GDEs. Wu et al[18] found that SURF4 was one of the key nodes of bone morphogenetic proteins induced osteogenic differentiation of mesenchymal stem cells and may be involved in the exosome signaling pathway. In summary, as a transmembrane protein of the cargo receptor that is located at ERGIC and the ER, SURF4 is a circulating protein in the early secretion pathway. It is an essential gene for maintaining the basic life activities of cells and early embryonic development. SURF4 is expected to become a new diagnostic and treatment target in cardiovascular and cerebrovascular diseases, osteogenic diseases, microbial infections, tumors, and other diseases. Current studies indicate that SURF4 is a potential oncogene whose overexpression can lead to cell proliferation and migration, maintain anchored independent growth, and shorten the overall survival of patients. SURF4 is a molecular contributor to cancer progression and may be a new target for drug therapy. Funding This work was supported by the Scientific Research Fund of Jiangsu Provincial Department of Health (No. H2017075) and Taizhou People's Hospital Innovation Team Fund (No. CXTDB201904). Conflicts of interest None.