The human body relies on genes and proteins as fundamental building blocks. Among these, UNC93B1 is a key protein in the immune system. Its proper function is necessary for the body’s defense mechanisms, protecting against various threats.
Understanding UNC93B1
UNC93B1 is a protein encoded by the UNC93B1 gene. It is a multi-pass transmembrane protein, meaning it spans the cell’s internal membranes multiple times. UNC93B1 primarily resides within the endoplasmic reticulum (ER), a network of membranes involved in protein and lipid synthesis. From the ER, UNC93B1 helps move specific immune receptors to their correct locations within the cell.
This protein acts as a “chaperone” for a specific group of immune receptors called Toll-like Receptors (TLRs). UNC93B1 guides these TLRs from the ER to specialized compartments within the cell called endosomes. This precise movement is necessary for the TLRs to function correctly, ensuring they are positioned to detect foreign invaders. Its ability to regulate the transport and stability of these receptors highlights its role in the immune system.
UNC93B1’s Role in Immune Response
UNC93B1 plays a significant role in the innate immune response by overseeing endosomal Toll-like Receptors (TLRs), including TLR3, TLR7, TLR8, and TLR9. These TLRs detect nucleic acids from pathogens, such as viral double-stranded RNA (dsRNA) or bacterial and viral DNA. UNC93B1 helps these receptors move from the endoplasmic reticulum into endolysosomes, where they bind to pathogen-derived nucleic acids. Their precise localization within endosomes is necessary to distinguish foreign nucleic acids from the body’s own genetic material, preventing inappropriate immune activation.
UNC93B1 ensures proper TLR activation and stability upon encountering pathogens. For example, it helps activate TLR3 by viral dsRNA, which can then prime TLR9 responsiveness. UNC93B1 also helps maintain the protein expression levels of TLR3 and TLR7 in various primary immune cells, and to a lesser extent, TLR9.
Upon activation, these TLRs trigger intracellular signaling pathways that lead to the production of various immune molecules. TLR3 activation, facilitated by UNC93B1, leads to type I interferon (IFN) responses, which are powerful antiviral defenses. Similarly, endosomal TLR7 and TLR9, also dependent on UNC93B1, activate IRF5 and type I IFN pathways. This ensures the immune system effectively recognizes and responds to microbial threats.
When UNC93B1 Doesn’t Work Properly
When the UNC93B1 gene or its encoded protein malfunctions, it can have serious consequences for human health. Mutations or deficiencies in UNC93B1 can lead to severe immunodeficiencies, making individuals highly vulnerable to certain infections. For instance, a deficiency in UNC93B1 has been linked to an impaired interferon-alpha/beta and -lambda antiviral response.
UNC93B1 dysfunction is associated with herpes simplex encephalitis (HSE), a severe form of viral encephalitis. Individuals with a deficiency in UNC93B1 exhibit impaired cellular responses to Herpes simplex virus type 1 (HSV-1), leading to a reduced ability to produce type I interferons, which are important for antiviral defense. This susceptibility to HSE highlights UNC93B1’s specific role in the TLR3 pathway, which is involved in detecting viral nucleic acids.
Beyond immunodeficiency, dysregulation of UNC93B1 can also contribute to autoimmune conditions. Mutations that result in a “gain-of-function” for UNC93B1 can lead to overactive immune responses, causing the immune system to mistakenly attack the body’s own tissues. Such mutations have been identified in patients with systemic lupus erythematosus (SLE) and chilblain lupus, where they enhance the signaling of TLR7 and, to a lesser extent, TLR8. This hyperactivation of TLRs can lead to chronic inflammation and the development of autoimmune symptoms like rashes, arthritis, and organ involvement.