The Diverse Role of CUB and Sushi Multiple Domains 1 (CSMD1) in Human Diseases

Abstract

CUB and Sushi Multiple Domains 1 (CSMD1), a tumour suppressor gene, encodes a large membrane-bound protein including a single transmembrane domain. This transmembrane region has a potential tyrosine phosphorylation site, suggesting that CSMD1 is involved in controlling cellular functions. Although the specific mechanisms of action for CSMD1 have not yet been uncovered, it has been linked to a number of processes including development, complement control, neurodevelopment, and cancer progression. In this review, we summarise CSMD1 functions in the cellular processes involved in the complement system, metastasis, and Epithelial mesenchymal transition (EMT) and also in the diseases schizophrenia, Parkinson’s disease, and cancer. Clarifying the association between CSMD1 and the aforementioned diseases will contribute to the development of new diagnosis and treatment methods for these diseases. Recent studies in certain cancer types, e.g., gastric cancer, oesophageal cancer, and head and neck squamous cell carcinomas, have indicated the involvement of CSMD1 in response to immunotherapy.

Tumor suppressor role of the complement inhibitor CSMD1 and its role in TNF-induced neuroinflammation in gliomas

“…Gliomas are aggressive brain tumors that present significant challenges in treatment and prognosis despite advances in therapeutic strategies. The tumor suppressor role of CSMD1 has been demonstrated in several cancers [ 33 ] but its role in glioma has not been determined. In this study, we first revealed that elevating CSMD1 expression in glioma cell lines significantly suppressed crucial malignant traits including cancer cell proliferation, migration, invasion, and the properties linked with the cancer stem cell phenotype.…”

Complement C4-deficient mice have a high mortality rate during PTZ-induced epileptic seizures, which correlates with cognitive problems and the deficiency in the expression of Egr1 and other immediate early genes

“…Despite CR1 being mainly expressed in erythrocytes, B cells, macrophages, and granulocytes ( Khera and Das, 2009 ), the new type 1 complement receptor CSMD1 was found to be highly expressed in the CNS and epithelial cells ( Kraus et al, 2006 ). CSMD family consists of CSMD1, CSMD2, and CSMD3 members, and CSMD1 is the most well-studied member ( Ermis Akyuz and Bell, 2022 ). Similar to CR1, CSMD1 was shown to bind C4b and C3b to promote their degradation by Factor I ( Escudero-Esparza et al, 2013 ), and it is highly expressed in the CNS in 80% of GABAR-positive synapses and 40% of NMDAR-positive synapses ( Baum et al, 2020 ).…”

“…CSMD1 and CSMD2 polymorphisms were associated with SZ ( Håvik et al, 2011 ; Rose et al, 2013 ), while CSMD3 was associated with both SZ and ASD ( Mizukami et al, 2016 ). It was shown that CSMD1 could bind and inhibit RTKs such as EGFR (potent inducer of IEGs) and CSMD1 can also modulate TGFβ receptor signaling ( Gialeli et al, 2021 ; Ermis Akyuz and Bell, 2022 ). Although both EGFR and TGFβRs are expressed in the CNS ( Dobolyi et al, 2012 ; Romano and Bucci, 2020 ), neuronal cells have other important RTKs such as TrkA and TrkB neurotrophic receptors, that bind BDNF and NGF, respectively ( Haddad et al, 2017 ).…”

“…We believe this happens because, in the case of C4 deficiency, the activation of both C4 and C3 is affected (both C4b and C3b fragments are missing), while in the case of C3 deficiency, activation of C4 is still intact (C4b fragments are still present). This is especially important if we remember the fact that CR1 receptors (CR1/CD35 and CSMDs) bind both C4b and C3b ( Khera and Das, 2009 ; Ermis Akyuz and Bell, 2022 ). In support of this assumption, it was found that the level of C4 remains high in the CNS of C3-deficient mice, while C4B –/– mice have a decrease in both C3 and C4 in the CNS ( Yilmaz et al, 2021 ).…”

Whole Genome Sequencing Revealed Inherited Rare Oligogenic Variants Contributing to Schizophrenia and Major Depressive Disorder in Two Families

“…CSMD1 encodes the CUB and Sushi multiple domains 1 protein, a transmembrane protein that controls several cellular functions. CSMD1 has been linked to several diseases, such as cancer, Parkinson's disease, and schizophrenia [41], indicating that CSMD1 dysfunction has various clinical effects. Several genetic studies reported that CSMD1 was associated with schizophrenia [42][43][44][45].…”