UXT at the crossroads of cell death, immunity and neurodegenerative diseases

Abstract

The ubiquitous expressed transcript (UXT), a member of the prefoldin-like protein family, modulates regulated cell death (RCD) such as apoptosis and autophagy-mediated cell death through nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), P53, P62, and methylation, and is involved in the regulation of cell metabolism, thereby affecting tumor progression. UXT also maintains immune homeostasis and reduces proteotoxicity in neuro-degenerative diseases through selective autophagy and molecular chaperones. Herein, we review and further elucidate the mechanisms by which UXT affects the regulation of cell death, maintenance of immune homeostasis, and neurodegenerative diseases and discuss the possible UXT involvement in the regulation of ferroptosis and immunogenic cell death, and targeting it to improve cancer treatment outcomes by regulating cell death and immune surveillance.

Keywords: UXT; apoptosis; autophagy; immunity; neurodegenerative disease.

Figure 1

UXT and NF-κB signaling pathway: When TNF-α binds to TNFR1 and UXT-V1 binds to TRAF2, apoptosis is inhibited by inhibiting the formation of complex- II by inhibiting FADD recruitment. UXT-V1 binds to the SARM on the mitochondrial membrane and inhibits the activity of casepase8, thereby inhibiting cell apoptosis. UXT-V2 binds to SARM up-regulating the activity of casepase8 and promoting apoptosis. UXT-V2 acts as an NF-κB enhancer to regulate the transcription of downstream genes in the NF-κB signaling pathway. EZH1 and LRP-16 participate in the composition of the NF-κB enhanceosome.

Figure 2

UXT and the P53 signaling pathway: UXT-V2 inhibits P53 by promoting ubiquitin degradation of P53 through MDMX. Down-regulation of P53 activity leads to selective activation of NF-κB signaling pathway, up-regulation of HIF-1α expression, promotion of glycolysis gene GLUT-1/3, HK-2, LDHA, and ENO expression, and promotion of glycolysis. These changes promote cell proliferation. By binding to DNMT3B, UXT-V2 downregulates MEG3 by methylation and thus inhibits the P53 signaling pathway. When P53 is suppressed, apoptosis is inhibited and cell proliferation, migration and invasion are promoted.

Figure 3

UXT and methylation: HOXD9 acts on the UXT promoter to up-regulate UXT expression. UXT promotes methyltransferase activity with EZH2 in PRC2 and methylates the promoter of the tumor suppressor gene RND3/HOXA9. The expression of RND3/HOXA9 is down-regulated and promotes tumor cell proliferation, migration and colony formation.

Figure 4

UXT and autophagy: UXT-V2 can be combined with TSG101. When UXT-V2 is down-regulated, it promotes the binding of TSG101-containing vesicles to lysosomes and promotes the degradation of CEP55. At the same time, the expression of LC3-II was up-regulated. UXT interact with mTOR, When UXT-V2 is down-regulated, autophagy promotes genetic Atg4b/Uvrag/Wipi1/Vps11/Atg9b/Tfeb/Vps18 expression are suppressed. And then inhibit autophagy. P62 can form a strip α-helical structure. UXT-V2 promotes the interweaving of P62 into a network, increases the binding sites of P62 and LC3, and promotes the autophagy degradation of SOD1 aggregates and STING1.

Figure 5

UXT promotes immune response: ​As one of the components of the MAVS signalosome, UXT-V1 promotes the nuclear translocation of IRF3 and NF-κB by binding to TRAF3, thus promoting innate immune response. UXT-V2 can be phosphorylated by BGLF4, disrupting its NF-κB enhanceosome function.

Figure 6

UXT inhibits the immune response: ​UXT-V2 negatively modulates the cGAS-STING1 signaling pathway by promoting the autophagy degradation of STING1 mediated by P62. These changes lead to a down-regulation of the type I IFN expression.

Figure 7

UXT regulates the tumor microenvironment: ​UXT-V2 promotes glycolysis by selectively activating the NF-κB signaling pathway by inhibiting the P53 signaling pathway. Glycolysis is promoted to increase lactate production and to acidify the TME. When UXT-V2 expression is up-regulated in Tregs, FOXP3 mRNA and protein levels are also up-regulated. UXT-V2 can also help maintain the inhibitory phenotype of Treg by binding to FoxP3 and stabilizing FOXP3 binding to IL-2/CTLA-4/CD25 promoters.

Figure 8

UXT regulates the degradation of SOD1 protein aggregates in ALS: UXT-V2 promotes autophagy degradation of P62 - mediated SOD1 protein aggregates. UXT-V2 promotes endolysosomal trafficking of SOD1 protein aggregates by binding to ALS2.

Figure 9

UXT regulates neuroinflammation in ALS: UXT-V2 down regulates the expression of type I IFN by autophagy degradation of STING1 mediated by P62. UXT-V2 promoted the inhibitory phenotype of Tregs by binding to FOXP3. Together, they improve neuroinflammation in neurodegenerative diseases.