Rab GTPases: Switching to Human Diseases
Abstract
:1. Introduction
2. Rab Proteins in Neurodegenerative Diseases
2.1. Alzheimer’s Disease
2.2. Parkinson’s Disease
2.3. Amyotrophic Lateral Sclerosis
2.4. Charcot–Marie–Tooth 2B
3. Rab Proteins in Cancer
4. Rab Proteins in Immune Diseases and Infections
4.1. Infections
4.2. Immune Disorders
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Rab Protein | Rab Alterations Associated with the Disease | References | |
---|---|---|---|
Alzheimer’s Disease (AD) | Rab6 | Increased levels but decrease of active, membrane-associated Rab6 and defective recycling of vesicle | [74,75] |
Rab5 | Upregulated and over-activated | [76,77] | |
Rab7a | Upregulated | [76,77] | |
Rab4 | Upregulated | [77] | |
Rab27 | Upregulated | [77] | |
Rab10 | Phosphorylated and upregulated | [78,79] | |
Rab11 | Genetic association of Rab11 with late-onset AD; affects Aβ production | [80] | |
Parkinson’s Disease (PD) | Rab39b | Loss-of-function mutations | [81,82,83,84] |
Rab8a/b | Defective phosphorylation by pathogenic leucine-rich repeat kinase 2 (LRRK2) leading to centrosomal defects and influencing neurite outgrowth, cell polarization and migration. Abolished phosphorylation in PTEN-induced putative kinase (PINK1)-caused PD | [85,86] | |
Rab7a | Decreased activity; defective endosomal trafficking and degradation in LRRK2-caused PD | [87,88] | |
Rab29 (Rab7L1) | Upregulated and present in a risk locus for sporadic PD; over activates LRRK2 PD-mutants by increasing their recruitment to the Golgi | [89,90,91] | |
Amyotrophic Lateral Sclerosis (ALS) | Rab1 | Dysfunctional in sporadic ALS; its effector C9orf72 is mutated in ALS, resulting in a decreased autophagy. Rab1-dependent endoplasmic reticulum (ER)-Golgi transport inhibited in superoxide dismutase 1 (SOD1), TAR DNA binding protein (TDP-43), and Fused in Sarcoma (FUS)-associated ALS. | [92,93] |
Charchot–Marie–Tooth 2B (CMT2B) | Rab7a | Missense mutations characterized by excessive activation that cause a reduced autophagic flux, premature neurotrophine receptor degradation, impaired axonal trafficking of the receptor, and inhibition of neurite outgrowth | [94,95,96,97,98] |
Huntington’s Disease (HD) | Rab11 | Decreased activity and defects in endosomal recycling | [99,100,101,102] |
Rab Protein | Rab Alterations Associated with Cancer | References |
---|---|---|
Rab5 | Overexpressed, promotes invasion by influencing FAK signaling and the extracellular signal-regulated kinase (ERK)/matrix metalloproteinase 2 (MMP2) pathway; required for hypoxia-driven tumor cell migration, invasion, and metastasis | [150,151,152,153] |
Rab11 | Hypoxia promotes Rab11-mediated trafficking of α6β4 integrin to the cell surface contributing to tumor cell invasion | [14] |
Rab39a | Overexpressed; genetic amplification of RAB39A-RXRB | [154] |
Rab1a | Overexpressed; promotes oncogenic growth by activating mammalian target of rapamycin complex 1 (mTORC1) signaling | [21,155] |
Rab35 | Somatic mutations; regulates endocytosis and recycling, contributing to phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) activation and promoting cell survival | [22] |
Rab25 | Altered expression: overexpression enhances cell migration and invasiveness by regulating α5β1 integrin trafficking. Downregulation possibly influences multiple pathways | [15,156,157,158,159] |
Rab40b | Overexpressed, mediates secretion of MMP2/9 thus promoting cancer invasion and metastasis | [160,161] |
Rab2a | Overexpressed; regulates the transport of membrane type 1 metalloproteinase (MT1-MMP) and E-cadherin and promotes invasion | [17] |
Rab22a | Overexpressed, involved in hypoxia-driven tumor migration, invasion and metastasis | [162] |
Rab23 | Altered expression: overexpression induces cell migration, invasion and proliferation by modulating Rac1 activity. Downregulation possibly affects the hedgehog signaling pathway | [163,164,165,166,167,168,169] |
Targeted Rab Protein | Mechanism | References | |
---|---|---|---|
Mycobacterium tuberculosis | Rab5 | Secretes a nucleoside diphosphate kinase that acts as GAP for Rab5, preventing early endosome antigen 1 (EEA1) recruitment. This arrests phagosome maturation | [183,184] |
Rab7a | Secretes a nucleoside diphosphate kinase that acts as GAP for Rab7a, preventing Rab-interacting lysosomal protein (RILP) recruitment. This inhibits lysosomal enzyme transport and phagosomal degradation | [184] | |
Chlamydia trachomatis | Rab5 | Secretes CT147, homologue of EEA1, that prevents endosomal fusion and bacterial degradation | [185] |
Broad-host Salmonella enterica | Rab32 | Delivers a Rab32 GAP and a Rab32-specific protease to neutralize the Rab32/ biogenesis of lysosome-related organelles complex-3 (BLOC-3) antimicrobial pathway | [186,187] |
Rab29 | Delivers a Rab29-specific protease | [188] | |
Rab38 | Delivers a Rab38-specific protease | [187] | |
Rab9 | Delivers SifA, an effector that sequesters Rab9, inhibiting the delivery of mannose 6-phosphate receptors (MPRs) and lysosomal enzymes to the Salmonella-containing vacuole (SCV) | [189] | |
Legionella pneumophila | Rab5 | Secretes a GEF for Rab5 and the effector VipD that prevents the binding of Rab5 to downstream effectors blocking endosomal trafficking and lysosomal degradation | [190,191] |
Rab21 | Secretes a GEF for Rab21 | [190] | |
Rab22 | Secretes a GEF for Rab22 and VipD that prevents the binding of Rab22 to downstream effectors blocking endosomal trafficking and lysosomal degradation | [190,191] | |
Rab1 | Secretes GEF for Rab1 to recruits Rab1 to SCV and effectors that regulate Rab1 cycle to create a replicative organelle | [192,193,194,195,196,197,198] |
Rab Protein | Alterations | Reference | |
---|---|---|---|
Griscelli syndrome | Rab27a | Mutations cause melanosome accumulation in melanocytes and uncontrolled T-lymphocyte and macrophage activation | [209] |
Choroideremia | Rab27a | Accumulation of unprenylated Rab27a causes defects in transport pathways regulated by Rab27a | [210] |
Crohn’s disease | Rab13 | Dislocated to the basolateral junctions in the intestinal epithelium, possibly affecting intestinal permeability | [212] |
Carpenter’s syndrome | Rab23 | Truncating and missense mutations | [213,214] |
Cone-Rod dystrophy | Rab28 | Nonsense mutations cause phagocytosis defects in cones | [215] |
X-linked mental retardation | Rab39b | Loss-of-function mutations lead to defective neurite growth cones and reduced presynaptic buttons | [126] |
Warburg Micro syndrome | Rab18 | Loss-of-function mutations in Rab18 or its GEFs | [216,217,218,219] |
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Guadagno, N.A.; Progida, C. Rab GTPases: Switching to Human Diseases. Cells 2019, 8, 909. https://doi.org/10.3390/cells8080909
Guadagno NA, Progida C. Rab GTPases: Switching to Human Diseases. Cells. 2019; 8(8):909. https://doi.org/10.3390/cells8080909
Chicago/Turabian StyleGuadagno, Noemi Antonella, and Cinzia Progida. 2019. "Rab GTPases: Switching to Human Diseases" Cells 8, no. 8: 909. https://doi.org/10.3390/cells8080909