ARL8B: A novel small G protein indispensable for equal chromosome segregation

Target Name: ARL8B

NCBI ID: G55207

ARL8B

ARL8B: A novel small G protein indispensable for equal chromosome segregation

Chromosome segregation is a critical process that ensures the genetic diversity in offspring produced by cell division. Equal chromosome segregation is particularly important for organisms with homoscedastic inheritance, such as humans, where abnormal chromosome segregation can lead to genetic disorders. Small G proteins (SGPs) play a crucial role in regulating chromosome segregation. In this article, we discuss the novel small G protein ARL8B and its potential as a drug target or biomarker.

Molecular Background

ARL8B (short for Arl8b) is a small G protein that belongs to the P21 subfamily of SGPs. P21 SGPs are involved in various cellular processes, including cell signaling, cell adhesion, and chromatin remodeling. ARL8B is characterized by its unique N-terminal domain, which contains a nucleotide-binding oligomerization (NBO) domain and a carboxy-terminal domain.

Function and Mechanism

ARL8B is essential for equal chromosome segregation in eukaryotic cells. During interphase, ARL8B interacts with the protein Cohesin, which is involved in the histone-associated nucleosome (HAN) complex. The HAN complex is responsible for ensuring that sister chromatids remain physically associated during the metaphase stage of cell division.

In addition to its role in chromosome segregation, ARL8B is involved in the regulation of gene expression. Several studies have shown that ARL8B can interact with various transcription factors, including T-cell factor (TGF-β), to promote the expression of target genes. This interaction between ARL8B and TGF-β highlights the potential of ARL8B as a drug target or biomarker for human diseases associated with abnormal chromosome segregation, such as cancer.

Drug Target Potential

ARL8B's unique mechanism of action and its interaction with TGF-β make it an attractive drug target. Activated TGF-β signaling has been implicated in various diseases, including cancer, neurodegenerative disorders, and developmental defects. By targeting ARL8B, researchers may be able to reduce TGF-β activity and improve chromosome segregation, leading to the prevention of disease.

Biomarker Potential

ARL8B may also serve as a biomarker for diseases associated with abnormal chromosome segregation. The ability of ARL8B to interact with TGF-β and its role in regulating gene expression make it a potential candidate for targeting diseases caused by disruptions in chromosome segregation. For example, ARL8B-deficient mice have been shown to have altered chromosome segregation and an increased risk of developing neurodegenerative disorders.

Pathway Analysis

ARL8B's involvement in the regulation of chromatin remodeling and the interaction with TGF-β raise questions about potential downstream targets. Chromatin remodeling is a complex process that involves the regulation of histone modifications, including acetylation and methylation. ARL8B's role in this process suggests that it may be involved in modifying chromatin structure and behavior.

Conclusion

In conclusion, ARL8B is a novel small G protein that plays a crucial role in equal chromosome segregation. Its interaction with TGF-β and the regulation of gene expression make it an attractive drug target or biomarker for diseases associated with abnormal chromosome segregation. Further research is needed to fully understand the role of ARL8B in chromosome segregation and its potential as a drug target or biomarker.

Protein Name: ADP Ribosylation Factor Like GTPase 8B

Functions: Small GTPase which cycles between active GTP-bound and inactive GDP-bound states (PubMed:15331635, PubMed:16537643). In its active state, binds to a variety of effector proteins playing a key role in the regulation of lysosomal positioning which is important for nutrient sensing, natural killer cell-mediated cytotoxicity and antigen presentation. Along with its effectors, orchestrates lysosomal transport and fusion (PubMed:16650381, PubMed:16537643, PubMed:28325809, PubMed:25898167, PubMed:27808481). Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility by recruiting PLEKHM2, which in turn recruits the motor protein kinesin-1 on lysosomes. Required for lysosomal and cytolytic granule exocytosis (PubMed:22172677, PubMed:29592961, PubMed:24088571). Critical factor involved in NK cell-mediated cytotoxicity. Drives the polarization of cytolytic granules and microtubule-organizing centers (MTOCs) toward the immune synapse between effector NK lymphocytes and target cells (PubMed:24088571). In neurons, mediates the anterograde axonal long-range transport of presynaptic lysosome-related vesicles required for presynaptic biogenesis and synaptic function (By similarity). Also acts as a regulator of endosome to lysosome trafficking pathways of special significance for host defense (PubMed:21802320). Regulates cargo trafficking to lysosomes by binding to PLEKHM1 and recruiting the HOPS subunit VPS41, resulting in functional assembly of the HOPS complex on lysosomal membranes (PubMed:16537643, PubMed:25908847). Plays an important role in cargo delivery to lysosomes for antigen presentation and microbial killing. Directs the intersection of CD1d with lipid antigens in lysosomes, and plays a role in intersecting phagosomes with lysosomes to generate phagolysosomes that kill microbes (PubMed:25908847, PubMed:21802320). Involved in the process of MHC II presentation. Regulates the delivery of antigens to lysosomes and the formation of MHC II-peptide complexes through the recruitment of the HOPS complex to lysosomes allowing the fusion of late endosomes to lysosomes (By similarity). May play a role in chromosome segregation (PubMed:15331635)

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