Promoting TTC4 and HSP70 interaction and translocation of annexin A7 to lysosome inhibits apoptosis in vascular endothelial cells

Abstract

We previously demonstrated that Tetraticopeptide 4 (TTC4) inhibited apoptosis in vascular endothelial cells (VEC) deprived of serum and fibroblast growth factor 2 (FGF‐2). In this study, we aimed to resolve the mechanism of TTC4 inhibiting VEC apoptosis. TTC4, predicted as a HSP70 co‐chaperone protein, may regulate the fate of cells by affecting the activity of HSP70, however, there is no experimental evidence showing the interaction of TTC4 and HSP70. Using Co‐immunoprecipitation (Co‐IP), we demonstrated that TTC4 interacted with HSP70. If HSP70 was knockdown, TTC4 no longer suppressed apoptosis. Furthermore, we found ABO, an inhibitor of annexin A7 (ANXA7) GTPase, could promote the interaction of TTC4 and HSP70 and the translocation of ANXA7 to lysosome. At the same time, ABO inhibited the interaction of HSP70 and ANXA7. Moreover, Akt, as a downstream effector of HSP70 was upregulated, and ANXA7 translocating to lysosome protected the stability of lysosomal membrane. Here, we discovered a special mechanism by which TTC4 inhibited apoptosis via HSP70 in VECs. On the one hand, increasing TTC4 and HSP70 interaction upregulated Akt that inhibited apoptosis. On the other hand, decreasing HSP70 and ANXA7 interaction promoted the translocation of ANXA7 to lysosome, which inhibited apoptosis through protecting the lysosomal membrane stability.

DNAJC12 causes breast cancer chemotherapy resistance by repressing doxorubicin-induced ferroptosis and apoptosis via activation of AKT

“…Several reports have shown that the Hsp70 level and its ATPase function could regulate the level and activity of AKT in different ways [ [40] , [41] , [42] , [43] , [44] ]. HSP70-induced AKT activation was involved in many drug-induced apoptosis processes in previous studies [ 45 , 46 ]. Heat shock 70-kDa protein 5 (HSPA5) increased the expression and activity of glutathione peroxidase 4 (GPX4) and thus inhibited ferroptosis [ 47 , 48 ].…”

TTC4 inhibits NLRP3 inflammation in rheumatoid arthritis by HSP70

“…He et al discovered that TTC4 and HSP70 interact to reduce apoptosis of vascular endothelial cells. 14 The present study investigated the expression of TTC4 mRNA in a model of RA. TTC4 gene reduced oxidative response and inflammation in a model of RA through the HSP70/NLRP3 pathway.…”

“…METTL3 reduced TTC4 gene stability. He et al discovered that TTC4 and HSP70 interact to reduce apoptosis of vascular endothelial cells 14 …”

“…As this gene has homology with some tumorigenesis-related genes in the TTC gene family, it is speculated that it may be potentially related to tumorigenesis. 14 TTC4 is expressed in the heart, brain, placenta, liver, skeletal muscle, and pancreas, with low expression in lung tissue. Further research on the relationship between the TTC4 gene and RA reveals the pathogenesis of the disease at the molecular level, which not only helps clinicians to predict the occurrence and development of the disease, but also provides a theoretical basis for RA diagnosis, treatment, and drug design.…”

“…The gene is present in band 1, short arm region 3 of human chromosome 1 (1p31) with 10 exons. As this gene has homology with some tumorigenesis‐related genes in the TTC gene family, it is speculated that it may be potentially related to tumorigenesis 14 . TTC4 is expressed in the heart, brain, placenta, liver, skeletal muscle, and pancreas, with low expression in lung tissue.…”