The Versatile Role of TMED Family Proteins: From Intracellular Transport to Disease Mechanisms

Introduction

Protein transport is a significant biological activity, it takes place in every cell in the human body and supports numerous functions crucial for health and growth. The proteostasis mechanisms are quite complex and involve several protein families, with the TMED family being among the key players. This family of proteins is well known for its membrane-active properties and evidences have indicated its involvement in several cellular activities. The TMED proteins play important roles in our development, metabolism, and immunity, the proteins are also implicated in various diseases and disorders including cancer.

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Fig. 1 TMED family in disease (Aber R., et al. 2019).

TMED Family

The TMED family, also referred to as the transmembrane emp24 domain-containing protein (TMED)/p24 family, constitutes a group of membrane proteins abundantly present in COPI- and COPII-coated vesicles, as well as in the membranes of the endoplasmic reticulum (ER) and cis-Golgi. This family, commonly known as p24 proteins due to their average molecular mass of 24 kDa, plays a crucial role in the early secretory pathway. In mammals, ten TMED family members have been identified, and categorized into α (TMED4, 9), β (TMED2), γ (TMED1, 3, 5, 6, 7), and δ (TMED10) based on phylogenetic analysis.

Structure and Function of the TMED Family

Despite minimal sequence homology, all TMED family members share a common structural arrangement. This includes a cytoplasmic area at the C-terminus, a flanking region, a coiled-coil domain, a single transmembrane domain, and an N-terminal Golgi-dynamics (GOLD) domain. The GOLD domain, traditionally considered critical for molecular recognition, has been found to mediate dimerization among TMED proteins.

TMED proteins play essential roles in COPI vesicle synthesis, the formation and organization of early secretory pathway structures, and the maintenance of the Golgi apparatus. They act as cargo receptors for the secretory route and participate in a quality control phase by identifying appropriately folded cargo. The interplay between different TMED family members is evident in their regulation of stability, with the knockdown or deletion of one protein affecting the expression of others.

In organ development, TMED proteins are expressed extensively, cooperating in processes such as early embryonic development, insulin biosynthesis, pancreatic β-cell secretion, and amyloid precursor protein metabolism. TMED2 and TMED10, for instance, regulate each other's stability and are involved in glycoylphosphatidylinositol (GPI)-anchored protein transport.

The Role of TMED Proteins in Common Human Diseases

Head and Neck Tumors

Head and neck squamous cell carcinoma (HNSC) is a prevalent malignancy, often diagnosed late with a poor prognosis. TMED2/9/10 expression levels have been found to be elevated in HNSC, indicating their potential involvement in tumor progression. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses suggest that these proteins contribute to intracellular transferase complex, protein transport, focal adhesion, and intracellular protein processing, impacting HNSC prognosis. Additionally, TMED7 and TMED3 have been identified as potential modifiers in nasopharyngeal and gliomas, respectively, emphasizing the multifaceted role of TMED proteins in different head and neck cancers.

Lung Cancer

TMED family genes have garnered attention in lung adenocarcinoma and non-small cell lung cancer (NSCLC). TMED2 and TMED3 have been implicated in lung adenocarcinoma development through the regulation of TLR4/NF-κB signaling and the Wnt/-catenin pathway, respectively. In NSCLC, TMED3 promotes cell growth via AKT regulation, making it a potential therapeutic target. TMED3 and TMED5 are also associated with lung squamous cell carcinoma, emphasizing their diverse roles in various lung cancer subtypes.

Breast Cancer

Breast cancer, a common malignancy in women, exhibits altered expression of TMED family genes. TMED3, TMED9, and TMED2 have been identified as potential prognostic markers and therapeutic targets in breast cancer. Their impact on cell migration, proliferation, and signaling pathways like Wnt/-catenin underscores their significance in breast cancer progression.

Reproductive System Tumors

TMED family genes show differential expression in ovarian, endometrial, cervical, and squamous cervical carcinomas. TMED2, TMED9, and TMED5 are implicated in ovarian cancer, suggesting their potential as prognostic biomarkers and therapeutic targets. In endometrial cancer, TMED3 knockdown inhibits tumor growth through the PI3K/AKT signaling pathway. TMED5 and TMED2 have been linked to aggressive development in squamous cervical carcinoma, providing insights into their roles in reproductive system malignancies.

Digestive System Tumors

TMED2 has emerged as a diagnostic and prognostic biomarker in esophageal adenocarcinoma, potentially related to promoter hypermethylation. Gastric carcinoma studies reveal associations with TMED3 and TMED5, emphasizing their roles in proliferation, invasion, and cisplatin resistance. In colorectal cancer, TMED3 and TMED9 exhibit complex interactions, influencing metastasis and tumor development. Additionally, TMED2 and TMED9 are implicated in hepatocellular carcinoma, highlighting their cell-type-specific functions.

Tumors of the Urinary System

TMED2 and TMED10 have been identified as potential biomarkers in prostate cancer, with high expression correlating with favorable prognosis. In clear cell renal cell carcinoma, TMED3 serves as a prognostic marker, shedding light on its potential role in renal malignancies.

Diabetes

Research shows that TMED6 and TMED10 are associated with diabetes. TMED6 is specifically expressed in pancreatic islets and may play a role in the control of insulin vacuoles. TMED10 is located on the negative membrane of pancreatic beta cells and is critical for the folding, fractionation, and release of insulin. Additionally, identified SNPs, including TMED2, suggest they may be associated with type 2 diabetes, providing avenues for future diabetes treatments.

Neurodegenerative Diseases

TMED9 and TMED10 have been associated with Alzheimer's disease, where they may play crucial roles in Aβ secretion and accumulation. Additionally, TMED10 is implicated in schizophrenia and Huntington's disease, providing insights into its role in neurodegenerative disorders.

Other Systemic Diseases

TMED2, TMED4, and TMED9 are implicated in various systemic diseases, including cardiovascular disorders, nephropathy, and xerostomia associated with Sjögren syndrome. These findings underscore the diverse impact of TMED family proteins on different physiological systems.

Conclusion

The TMED family, initially recognized for its involvement in intracellular transport, has emerged as a crucial player in various disease mechanisms, particularly cancer. Its diverse roles in organ development, tumor progression, and immune responses underscore its significance in cellular function. Further research on the TMED family promises novel insights into disease mechanisms and potential therapeutic targets, paving the way for advancements in clinical translation and targeted therapies.

References

1. Zhou L., et al. TMED family genes and their roles in human diseases. International Journal of Medical Sciences. 2023, 20(13): 1732.
2. Aber R., et al. Transmembrane emp24 domain proteins in development and disease. Genetics Research. 2019, 101: e14.