Chemokine-like Factor-like MARVEL Transmembrane Domain-containing Family in Autoimmune Diseases
The chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) is a group of proteins that play a significant role in the immune system. These proteins are widely expressed in various immune cells and are implicated in the pathogenesis of autoimmune diseases. This article provides a comprehensive overview of the CMTM family, focusing on their structure, expression, and involvement in autoimmune diseases. The CMTM family includes CKLF1 and CMTM1-8, each of which has unique characteristics and functions in immune regulation.
Introduction to the CMTM Family
The CMTM family was discovered by the Peking University Human Disease Gene Research Center. The initial member of this family, CKLF1, was isolated from phytohemagglutinin (PHA)-stimulated U937 cells. Subsequent research identified additional members of the family, CKLFSF1-8, using bioinformatics and reverse transcription polymerase chain reaction techniques. The Human Gene Nomenclature Committee later renamed these genes as CMTM1-8 due to their structural features, which lie between classical chemokines and members of the transmembrane 4 superfamily (TM4SF).
The CMTM family members are expressed in various tissues and immune cells, including peripheral blood mononuclear cells (PBMCs). They are involved in immune regulation and have been linked to the development of autoimmune diseases. The CMTM family is particularly notable for its role in T cell and B cell activation, chemotaxis, and the regulation of inflammatory responses.
CMTM Family Members and Their Functions in the Immune System
CKLF1
CKLF1 is located on chromosome 16q22.1 and has four exons and three introns. It has at least three alternative RNA splicing forms: CKLF2, CKLF3, and CKLF4. CKLF1 and CKLF3 are secreted proteins, while CKLF2 and CKLF4 are transmembrane proteins. CKLF1 is distinct from classical chemokines due to its unique structure, which includes a CC motif but lacks the additional C-terminal cysteines found in other CC subfamily members.
CKLF1 is a functional ligand for the C-C chemokine receptor 4 (CCR4). CCR4 is expressed on various immune cells, including CD4+ Th2 lymphocytes, dendritic cells (DCs), basophils, T cells, and platelets. The interaction between CKLF1 and CCR4 is crucial for the recruitment, homing, and education of activated leukocytes. CKLF1 also exhibits chemotactic activity for lymphocytes, macrophages, and neutrophils, and it plays a role in T cell activation.
CKLF1 has two secreted forms at the C-terminus, known as C19 and C27. C27 acts as an agonist of CCR4, while C19 acts as an antagonist. Both peptides can inhibit stromal cell-derived factor-1 (SDF-1)-induced chemotaxis by binding to CCR4 and activating the phosphatidyl inositol 3-kinase/protein kinase C pathway. C19 and C27 also enhance the capacity of immature DCs to induce T cell proliferation and interferon (IFN)-γ production.
CMTM1-5
CMTM1-4 is located in a gene cluster on chromosome 16q22.1. CMTM1 consists of seven exons and six introns and has 23 isoforms. It is highly expressed in testis and tumor tissues and may play a role in spermatogenesis or testicular development and tumorigenesis. CMTM2 is tightly linked with CMTM1 and is expressed in bone marrow and peripheral cells, including CD4+ T cells. It negatively regulates HIV-1 transcription in Jurkat and U937 cells by targeting the AP-1 and cyclic AMP response element binding (CREB) signaling pathways.
CMTM3 is highly expressed in the immune system and the male reproductive system. It is predominantly expressed in resting B lymphocytes, CD4+ T lymphocytes, and monocytes. CMTM3 can be released via exosomes and is involved in immune regulation. CMTM4 has three transcript variants and is a regulator of the programmed cell death-ligand 1 (PD-L1) protein. CMTM5 is located on chromosome 14q11.2 and is expressed in the granulocyte system. It may have immune-related functions and is secreted via a vesicle-mediated secretory pathway.
CMTM6-8
CMTM6-8 is located in a gene cluster on chromosome 3p22. CMTM6 is widely expressed and regulates anti-tumor immunity by maintaining the expression of PD-L1. CMTM7 is highly expressed in immune cells and links the B cell receptor (BCR) and B-cell linker protein (BLNK), initiating BLNK-mediated signal transduction in B cells. CMTM8 is structurally similar to TM4SF11 and is a negative regulator of epidermal growth factor (EGF)-induced signaling.
CMTM Family Members and Autoimmune Diseases
Autoimmune diseases are characterized by an immune response against self-antigens, leading to tissue damage and organ dysfunction. The CMTM family members are highly expressed in the immune system and have been implicated in various autoimmune diseases.
CKLF1
CKLF1 is associated with the pathogenesis of systemic lupus erythematosus (SLE), lupus nephritis (LN), rheumatoid arthritis (RA), and psoriasis. In SLE, CKLF1 is involved in neutrophil activation, IFN production, and B cell function. High expression of CKLF1 is related to the excessive involvement of inflammatory cells in chemotaxis, which mediates the immune inflammatory reaction process observed in LN.
In RA, CKLF1 is up-regulated in synovium and is associated with leukocyte infiltration into the synovial and chemokine network. CKLF1 may promote the development and progression of the inflammatory response and neo-angiogenesis in rheumatic diseases. In psoriasis, CKLF1 and CCR4 are highly expressed in psoriatic lesions. CKLF1 promotes the proliferation of microvascular endothelial cells and contributes to local inflammation through the MAPK/extracellular signal-regulated kinase (ERK) signaling pathway.
CMTM1
CMTM1 is down-regulated in rheumatoid arthritis synovial fibroblasts (RASFs) from patients treated with celastrol. Celastrol treatment mobilizes cytosolic Ca2+ in RASFs, suggesting a regulatory role for CMTM1 in Ca2+ signaling in RA.
CMTM2
CMTM2 is down-regulated in osteoarthritis (OA) patients compared with healthy controls. It is also differentially expressed in systemic sclerosis (SSc) peripheral blood cells and is up-regulated in the peripheral blood of ankylosing spondylitis (AS) patients.
CMTM3
CMTM3 is associated with Sjögren syndrome (SS). Elevated interaction of CMTM3 with autoantibodies is observed in SLE and primary SS (pSS) patients compared with healthy controls.
CMTM4
CMTM4 is associated with SLE and is identified as a novel candidate gene in an epistasis network model of exome data. The methylation status of the CMTM4 promoter is significantly different in SLE, RA, and pSS.
CMTM5
CMTM5 is hypermethylated in SLE and pSS but hypomethylated in RA. The antisense transcriptional activity of CMTM5 is much higher compared with sense transcription in SLE patients, suggesting a role in immunologic dysregulation.
CMTM6
CMTM6 is up-regulated in the neutrophils of anti-phospholipid syndrome (APS) patients. APS is characterized by arterial and/or venous thrombosis, pregnancy morbidity, and the presence of anti-phospholipid antibodies.
CMTM7 and CMTM8
Currently, CMTM7 and CMTM8 have been primarily identified in tumor and cardiovascular diseases. There are no relevant reports regarding their involvement in immunologic diseases.
Conclusion
The CMTM family plays a crucial role in the immune system and is implicated in the pathogenesis of various autoimmune diseases. CKLF1, in particular, has been extensively studied and is associated with SLE, LN, RA, and psoriasis. Other CMTM family members, such as CMTM1-8, also contribute to immune regulation and autoimmune diseases. Further research on the mechanisms of action of CMTM family members may lead to the development of new diagnostic and therapeutic strategies for autoimmune diseases.
doi.org/10.1097/CM9.0000000000000747
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