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As a newly discovered tuberculosis susceptibility gene, ASAP1 was first discovered by Cambridge University researchers through the GWAS (Genome-Wide Association Study). Afterward, the researchers conducted ASAP1 association studies and linkage analysis in different regions and ethnic groups and made a preliminary investigation of the function of ASAP1 and the mechanism affecting tuberculosis. Tuberculosis (TB) is one of the chronic infectious diseases that are currently a serious threat to human health. It is mainly caused by Mycobacterium tuberculosis (Mtb).
ASAP ribosylation factor-GTPase activating protein is a GTPase activating protein of ADP-ribosylation factors (Arf). The Arf family protein has a molecular weight of about 20 kDa and belongs to the small G protein. It is widely present in eukaryotes and is highly conserved in evolution. It is mainly involved in the regulation of membrane transport and the cytoskeleton. Arf has two binding states in cells, which bind to GTP as an active state and bind to GDP in an inactive state. Guanine nucleotide-exchange factor (GEF) and GTPase-activating protein (GAP) regulate the switch between the two binding states. ASAP1 belongs to the GAP protein that regulates Arf, also known as AMAP1 or Centaurinβ, and is a negative regulator of Arf. ASAP1 recognizes Arf·GTP and induces hydrolysis of GTP to form Arf·GDP, which inactivates Arf function.
Figure 1. Model for ASAP1 interaction with NM2A regulated by PIP2 and Arf. (Luo, R., et al. 2017)
In the model studied by Luo, PIP2, which binds to the PH-domain of AsAP1, promotes the binding of ARFGTP to ASAP1. ASAP1 undergoes a conformational change in interaction with NM2A, and subsequent AGFTTP hydrolysis induces ASAP1 to further promote a conformational change in NM2A activity and return ASAP1 to a conformation capable of another round of NM2A binding.
ASAP1 Function and Its Mechanism of Affecting Human Tuberculosis Susceptibility
ASAP1 functions mainly focus on intracellular endocytosis, intracellular vesicle transport, and cytoskeletal regulation, as well as tumor metastasis and spread. Tien et al. found that ASAP1 negatively regulates the signaling pathway of NF-kB, a transcription factor that regulates inflammatory responses in cells, suggesting that ASAP1 may become a new target for the treatment of inflammatory response. Ruggiero et al. found that a complex called KDELR, which is located in the Golgi apparatus, functions to degrade the extracellular matrix by increasing the cell structure of the foot process. The function of the foot process is dependent on the phosphorylation of ASAP1 by KDELR. The indirect reaction of ASAP1 is necessary for the degradation of the extracellular matrix. Davidson et al. found a mechanism of cell actin reorganization that relies on Arf6, a mechanism that enhances Salmonella infection. It is also pointed out that the equilibrium relationship between Arf GEFs and Arf GAPs is beneficial to the phagocytosis of Salmonella by host cells.
At present, the research on the mechanism of ASAP1 protein affecting the susceptibility of human tuberculosis is still in the exploration stage. Nowadays, it mainly focuses on the regulation of ASAP1 protein expression on the migration ability of immune cells, which in turn affects human susceptibility to TB. Curtis et al. detected the mRNA content of ASAP1 in Mtb-infected dendritic cells (DC) by qRT-PCR and found that its expression was significantly reduced. At the same time, the ability of infected DCs to migrate and phagocytic lysosome formation is reduced.
Tripathi et al. combined with flow cytometry and confocal microscopy revealed a significant reduction in the expression of β2 (CD18) integrin on the surface of Mtb-infected dendritic cells. At the same time, the αL (CD11a) and αM (CD11b) integrin subunits were also relatively reduced and showed a decrease in the adhesion of DC to the lung endothelial cell layer and a decrease in the migration ability of lymphokines. Eventually, the presentation of antigen by innate immune cells is weakened, and the occurrence of adaptive immunity is delayed, so that Mtb is more widely spread and distributed in vivo. Based on the above-mentioned susceptibility mechanism of TB and the function of ASAP1 protein, it is speculated that ASAP1 protein mainly affects the migration ability of immune cells, which in turn affects the immune process of pathogens.
ASAP1 Gene and Susceptibility to Tuberculosis
Curtis's genome-wide association analysis (GWAS) of 5,914 active TB patients and 6022 healthy volunteers from St. Petersburg, Russia, a high-incidence area in the world, found that 11 SNPs (Single Nucleotide Polymorphisms) of ASAP1 were significantly associated with TB susceptibility, and they all distributed in introns. The further statistical analysis was performed on 7 significant related SNPs, and the four most relevant SNP loci (rs10956514, rs1469288, rs2033059, rs4733781) were obtained. It is preliminarily concluded that the mechanism of ASAP1 affecting host susceptibility weakens the migration of DC and the degradation of extracellular matrix, slows down the innate immune process, and enhances the viability and invasiveness of intracellular parasites.
Hu applied the iMLDR method to 1115 western Han population and 914 Tibetan population to classify 7 SNP loci of ASAP1, and then combined with meta-analysis to further explore the correlation between ASAP1 and TB. Data comparison showed that there was no significant correlation between ASAP1 and TB susceptibility in the Chinese population. Miao et al. used TaqMan allelic discrimination in 355 Chinese patients with recent tuberculosis infection and 395 healthy people to analyze the two SNPs of ASAP1. It was found that ASAP1 and TB susceptibility were not significantly correlated in the Chinese population. This again illustrates the relationship between genetic polymorphism and disease that emphasizes ethnic differences.