Tetraspanins are a family of transmembrane proteins found on the surface of cells in all multicellular organisms. With 33 distinct members identified in humans, these proteins play fundamental roles in various biological processes, influencing how cells interact and behave.
Structure and Cellular Location
Tetraspanin proteins are characterized by four segments that cross the cell membrane. These segments create two extracellular loops (one short EC1 and one longer EC2), a short intracellular loop, and short tails at both ends inside the cell. The large extracellular loop contains conserved amino acid sequences, including four or more cysteine residues, with two forming a “CCG” motif.
While primarily on the cell surface, tetraspanins are also present in internal cellular compartments and exosomes, tiny vesicles released by cells. Tetraspanins function as “molecular facilitators” or “scaffolding proteins,” interacting directly with each other and with numerous other proteins and lipids.
These interactions lead to the formation of specialized areas on the cell membrane called “tetraspanin-enriched microdomains” (TEMs). TEMs serve as organized platforms that concentrate specific membrane proteins and signaling molecules. This clustering allows tetraspanins to bring together various molecular partners, such as integrins, growth factor receptors, and immunoglobulin superfamily members, influencing their localization and activity.
Core Functions in Cell Communication
Tetraspanins are involved in fundamental cellular processes that govern cell communication and interaction. They play roles in cell adhesion, which is how cells stick to each other and their surroundings. They also influence cell migration, controlling how cells move within tissues.
These proteins facilitate these processes by acting as organizers or scaffolds within TEMs. By localizing receptors and interacting partner proteins to specific membrane regions, tetraspanins can amplify cellular signaling pathways. For example, tetraspanins regulate integrins, cell surface receptors involved in cell-cell and cell-extracellular matrix adhesion, affecting their membrane compartmentalization and downstream signaling in response to migratory cues.
Tetraspanins also influence membrane organization and protein trafficking. They can regulate the activity of enzymes like matrix metalloproteinases (MMPs), which break down the extracellular matrix, a process relevant to cell migration and tissue remodeling. Through these actions, tetraspanins modulate a wide range of cellular activities, including cell proliferation and differentiation, by influencing the function and localization of their associated partners.
Roles in Health and Disease
Tetraspanins contribute to numerous physiological processes, including immune responses, development, and reproduction. In the immune system, tetraspanins on antigen-presenting cells organize immune receptors and adhesion molecules, influencing cell migration, antigen uptake, and the formation of immunological synapses, structures where immune cells communicate. For example, CD9 and CD151 on endothelial cells help arrange adhesion molecules like ICAM-1 and VCAM-1 into clusters, facilitating white blood cell recruitment during inflammation.
In reproduction, specific tetraspanins are involved in sperm-egg fusion, a necessary step for fertilization. For instance, CD9 on the oocyte surface optimizes microvilli, tiny projections that play a role in capturing sperm.
When tetraspanin function is disrupted, it can contribute to various disease states. In cancer, tetraspanins influence tumor progression, including metastasis and tumor growth. Some tetraspanins, like CD151 and Tspan8, are associated with increased cancer cell migration, invasion, and angiogenesis, the formation of new blood vessels that feed tumors. Conversely, CD9 and CD82 have been linked to tumor suppression.
Tetraspanins also play a role in viral infections. Viruses like HIV and influenza exploit tetraspanins to enter host cells, replicate, and spread. For instance, HIV assembles and buds through membrane areas enriched in tetraspanins such as CD9, CD63, CD81, and CD82. Their presence in viral particles can influence virus-induced membrane fusion.
In neurological disorders, tetraspanins like Tspan7 impact the formation of dendritic spines and glutamatergic synaptic transmission, which are related to learning and memory. Mutations in the gene encoding Tspan7 have been linked to X-linked intellectual disability, affecting excitatory synapse structure and function. Tetraspanins also regulate ADAM10, an enzyme involved in Alzheimer’s disease pathology.
Research Directions and Therapeutic Outlook
Tetraspanins are a significant area of scientific investigation due to their involvement in cellular processes and disease. Researchers are exploring their potential as biomarkers for disease diagnosis and prognosis. For example, elevated levels of exosomal tetraspanin 9 (TSPAN9) have been associated with lymph node and distant metastasis in colorectal cancer, suggesting its potential as a diagnostic marker.
Ongoing efforts aim to develop therapeutic strategies that target tetraspanins. This includes using monoclonal antibodies, small interfering RNAs (siRNAs), or soluble protein fragments to modulate their function. For instance, interventions targeting CD151 have been explored as a potential therapeutic approach against influenza A viruses.
The aim is to develop treatments for various conditions, particularly in cancer and infectious diseases. While many of the 33 mammalian tetraspanins are minimally studied, understanding their specific functions and interactions continues to expand, paving the way for future therapeutic developments.