Ubiquitination-Dependent Regulation of Small GTPases in Membrane Trafficking: From Cell Biology to Human Diseases

Abstract

Membrane trafficking is critical for cellular homeostasis, which is mainly carried out by small GTPases, a class of proteins functioning in vesicle budding, transport, tethering and fusion processes. The accurate and organized membrane trafficking relies on the proper regulation of small GTPases, which involves the conversion between GTP- and GDP-bound small GTPases mediated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Emerging evidence indicates that post-translational modifications (PTMs) of small GTPases, especially ubiquitination, play an important role in the spatio-temporal regulation of small GTPases, and the dysregulation of small GTPase ubiquitination can result in multiple human diseases. In this review, we introduce small GTPases-mediated membrane trafficking pathways and the biological processes of ubiquitination-dependent regulation of small GTPases, including the regulation of small GTPase stability, activity and localization. We then discuss the dysregulation of small GTPase ubiquitination and the associated human membrane trafficking-related diseases, focusing on the neurological diseases and infections. An in-depth understanding of the molecular mechanisms by which ubiquitination regulates small GTPases can provide novel insights into the membrane trafficking process, which knowledge is valuable for the development of more effective and specific therapeutics for membrane trafficking-related human diseases.

Remodeling of the protein ubiquitylation landscape in the aging vertebrate brain

“…Despite the overall trend of increased ubiquitylation with aging, a fraction of sites showed decreased ubiquitylation (Figure 1E). When assessing which cellular component categories were affected by these changes, GO enrichment analysis revealed that the myelin sheath, mitochondrion, and GTPase complex showed an increase in ubiquitylation, the latter in agreement with a previous report (Lei et al, 2021) (Figure 1E). In contrast, proteins belonging to the synaptic compartment were enriched among those showing decreased ubiquitylation with aging (Figure 1E).…”

Adaptation to ARF6-depletion in KRAS-driven PDAC is abolished by targeting TLR2

“…In general, a ubiquitination-dependent regulation is important for balancing MyD88-dependent and –independent pathways which signal through TRIF (conditionally TRIF3 or TRIF6), TRAMs and TAK. 30 While it is not common for TLR2 to signal in a MyD88-independent pathway, within the scope of this study, we found little evidence to show that TLR2 compensation for ARF6 loss was being mediated by MyD88. Only one study has identified that during infection by Porphyromonas gingivalis , a gram negative bacteria, TLR2 can upregulate TNFα and cytokines in a MyD88-independent manner.…”

“…Additionally, ARF6 function is regulated through ubiquitination which further impacts cellular migration and invasion. 29,30 Importantly on day 7, we observed an enrichment of cell cycle related terms surround the regulation of mitosis and chromosomal segregation (Figure 2 A), which we did not observe upon shASAP1 treatment (Supplementary Figure S2 B). These terms align with our findings that PDAC cells subject to ARF6-depletion, but not ASAP1-depletion, produce an adaptive proliferation response starting at day 7 (Figure 1 C).…”