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Arginylated HSPA5 and MUL1-mediated sequential ubiquitination collaborate in promoting AKT lysosomal degradation
- Author(s)
- 김효정
- Advisor
- 김철호
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2023-08
- Language
- eng
- Keyword
- AKT; HSPA5; MUL1; USP7; arginylation; ubiquitination
- Alternative Abstract
- Aberrant activation of AKT is a common occurrence in cancer and plays a role in controlling cell survival, proliferation, metabolism signals, tumor progression, and metastasis. Most studies on AKT degradation have focused on the ubiquitin-proteasome system (UPS). The aim of this research is to investigate the correlation between the consecutive ubiquitination of lysine (K) residues K284 to K214 in AKT and the arginylated form of HSPA5. This modification directs AKT to the autophagosome for degradation through the autophagy-lysosomal pathway (ALP) during proteotoxic stress. Our findings show that the sequential ubiquitination is a prerequisite step for degradation of the non-proteasomal proteolysis pathway. However, the mechanisms by which the ubiquitinated AKT is selectively recognized and delivered into the autophagosome remain unclear. In this mechanism, the transition from proteasomal to lysosomal degradation is hypothesized to occur by modifying the ubiquitination sites of AKT to include both K284 and K214. This modification leads to the formation of R-HSPA5-AKT complexes, which are then targeted to the autophagosome for degradation. Our results show that proteasomal inhibitor (PI) induces cytosolic accumulation of R-HSPA5 by ATE1-encoded Arg-tRNA transferase in a reactive oxygen species-dependent manner. The interaction between fully ubiquitinated AKT and R-HSPA5 facilitates the targeting of AKT to autophagic vacuoles, as indicated by its colocalization with p62/SQSTM1. Notably, this process involves the selective utilization of K48-linked ubiquitination of AKT by MUL1, which is hijacked by R-HSPA5 for subsequent degradation within lysosomes. Supporting this observation, it was found that in MUL1 knockout cells, AKT remained stable despite the induction of R-HSPA5 under proteotoxic stress. In contrast, the ubiquitin specific peptidase 7 (USP7) deubiquitinated and thereby stabilized AKT. MUL1-mediated AKT degradation involved both the UPS and ALP. Our investigation revealed that the lysosomal degradation of AKT, induced by PI treatment, is a result of the intricate interplay between two key processes: sequential ubiquitination mediated by MUL1 and protein quality control dependent on R-HSPA5.
- Fulltext
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- Graduate School of Ajou University > Department of Molecular Science and Technology > 4. Theses(Ph.D)
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