Rab21 Protein Is Degraded by Both the Ubiquitin-Proteasome Pathway and the Autophagy-Lysosome Pathway

Abstract

Rab21 is a GTPase protein that is functional in intracellular trafficking and involved in the pathologies of many diseases, such as Alzheimer’s disease (AD), glioma, cancer, etc. Our previous work has reported its interaction with the catalytic subunit of gamma-secretase, PS1, and it regulates the activity of PS1 via transferring it from the early endosome to the late endosome/lysosome. However, it is still unknown how Rab21 protein itself is regulated. This work revealed that Rab21 protein, either endogenously or exogenously, can be degraded by the ubiquitin-proteasome pathway and the autophagy-lysosome pathway. It is further observed that the ubiquitinated Rab21 is increased, but the total protein is unchanged in AD model mice. We further observed that overexpression of Rab21 leads to increased expression of a series of genes involved in the autophagy-lysosome pathway. We speculated that even though the ubiquitinated Rab21 is increased due to the impaired proteasome function in the AD model, the autophagy-lysosome pathway functions in parallel to degrade Rab21 to keep its protein level in homeostasis. In conclusion, understanding the characters of Rab21 protein itself help explore its potential as a target for therapeutic strategy in diseases.

Diallyl Trisulfide, a Major Bioactive Constituent of Garlic, Promotes Colonic Mucosal Healing in Ulcerative Colitis through Accelerating Focal Adhesion Assembly and Consequent Epithelial Cell Migration via the Rab21‐Integrin β1‐Fak Pathway

“…Rab21, a member of the Ras superfamily of small GTPases, can bind to the 𝛼 subunit of integrin, promote its endocytosis to early endosomes, and alter the localization of integrins in cells. [16][17][18][19] To recognize how DATS increases the endocytosis of integrin 𝛽1 in colonic epithelial cells, effect of DATS on the expression of Rab21 was examined. The results showed that DATS had no evident impact on the mRNA and protein expression of Rab21 in NCM 460 cells (Figure 7D).…”

Upregulation of UBR1 m6A Methylation by METTL14 Inhibits Autophagy in Spinal Cord Injury

“…Interestingly, our GSE2599 dataset prediction and preliminary experiments revealed a low expression of UBR1 in SCI rats. Meanwhile, ubiquitination and autophagy, two predominant intracellular degradation pathways, are distinct in their mechanisms but inextricably connected in controlling protein quality and maintaining cellular homeostasis ( P. Liu et al, 2022 ). A recently published article demonstrated that UBR1 facilitates the clearance of misfolded MLC1 during Ca 2+ stress by eliciting p62-mediated selective autophagy ( B.B.…”