Rab18: new insights into the function of an essential protein

Dejgaard, Selma Yilmaz; Presley, John F.

doi:10.1007/s00018-019-03050-3

Cited by 32 publications

(28 citation statements)

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“…RAB3GAP1 and RAB3GAP2 form a heterodimer that (despite the name) is a guanine nucleotide exchange factor that activates Rab18 (Gerondopoulos et al, 2014), and TBC1D20 has been reported as a GTP-activating protein that inactivates Rab18, suggesting a common disease mechanism involving Rab18 signaling (Handley et al, 2015). These proteins have roles in ER organization, ER-LD tethering, secretion, and autophagy (including in neurons) (Nevo-Yassaf et al, 2012;Liegel et al, 2013;Gerondopoulos et al, 2014;Sidjanin et al, 2016;Xu et al, 2018;Dejgaard and Presley, 2019;Nian et al, 2019). Recruitment of Rab18 to ER by Rab3GAP is essential for a normal ER tubular network, and this is disrupted by disease-causing mutations (Gerondopoulos et al, 2014), making ER a potential site for WRBM pathology.…”

Section: Warburg Micro Syndrome (Wrbm)mentioning

confidence: 99%

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

2020

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The physical continuity of axons over long cellular distances poses challenges for their maintenance. One organelle that faces this challenge is endoplasmic reticulum (ER); unlike other intracellular organelles, this forms a physically continuous network throughout the cell, with a single membrane and a single lumen. In axons, ER is mainly smooth, forming a tubular network with occasional sheets or cisternae and low amounts of rough ER. It has many potential roles: lipid biosynthesis, glucose homeostasis, a Ca 2+ store, protein export, and contacting and regulating other organelles. This tubular network structure is determined by ER-shaping proteins, mutations in some of which are causative for neurodegenerative disorders such as hereditary spastic paraplegia (HSP). While axonal ER shares many features with the tubular ER network in other contexts, these features must be adapted to the long and narrow dimensions of axons. ER appears to be physically continuous throughout axons, over distances that are enormous on a subcellular scale. It is therefore a potential channel for long-distance or regional communication within neurons, independent of action potentials or physical transport of cargos, but involving its physiological roles such as Ca 2+ or organelle homeostasis. Despite its apparent stability, axonal ER is highly dynamic, showing features like anterograde and retrograde transport, potentially reflecting continuous fusion and breakage of the network. Here we discuss the transport processes that must contribute to this dynamic behavior of ER. We also discuss the model that these processes underpin a homeostatic process that ensures both enough ER to maintain continuity of the network and repair breaks in it, but not too much ER that might disrupt local cellular physiology. Finally, we discuss how failure of ER organization in axons could lead to axon degenerative diseases, and how a requirement for ER continuity could make distal axons most susceptible to degeneration in conditions that disrupt ER continuity.

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Section: Warburg Micro Syndrome (Wrbm)mentioning

confidence: 99%

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

2020

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“…have shown that STAT5 controls, directly or indirectly, the expression of multiple milk protein genes and regulatory molecules involved in the lactation process (Yamagi et al, 2013). These include, in addition to the β-casein and Wap genes, Adph required for CLD maturation in the mammary tissue and Rab18 implicated in CLD maturation and transport in lipogenic cells (Russel et al, 2011;Dejgaard and Presley, 2019).…”

Section: Loss Of Rab6a Led To a Decreased Activation Of Stat5 In The mentioning

confidence: 99%

RAB6 GTPase is a crucial regulator of the mammary secretory function controlling STAT5 activation

Cayre

Faraldo

Bardin

et al. 2020

Preprint

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Running title: RAB6 in mammary secretory function Key words: RAB6 GTPase, mammary gland, luminal secretory cells, STAT5, PRL signaling SUMMARY STATEMENTThis study reveals a role for the Golgi-associated RAB GTPases, RAB6A/A', in the lactogenic function of the mammary gland. ABSTRACTThe Golgi-associated RAB GTPases, RAB6A and RAB6A', regulate anterograde and retrograde transport pathways from and to the Golgi. In vitro, RAB6A/A' have been reported to be involved in several cellular functions, including, in addition to transport, cell division, migration, adhesion and polarity. However, their role remains poorly described in vivo, in particular in epithelial tissues. Here, we generated BlgCre; Rab6a F/F mouse presenting a specific deletion of Rab6a in the mammary luminal secretory lineage during gestation and lactation. Rab6a loss severely impaired the differentiation, maturation and maintenance of the secretory tissue, compromising lactation. It led to a decreased activation of STAT5, a key regulator of the lactogenic process primarily governed by prolactin. Data obtained with a human mammary epithelial cell line suggested that defective STAT5 activation might originate from a perturbed transport of the prolactin receptor, altering its membrane expression and signaling cascade. Despite the major functional defects observed upon Rab6a deletion, the polarized organization of the mammary epithelial bilayer was preserved.Altogether, our data reveal a crucial role for RAB6A/A' in the lactogenic function of the mammary gland. They also suggest that the trafficking pathways controlled by RAB6A/A' depend on cell type specialization and tissue context.

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“…The syndrome is characterized by mental and physical disabilities including severe to profound intellectual impairment, microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, spastic diplegia, hypogonadism, craniofacial dysmorphism, and cerebral malformations, in particular corpus callosum hypoplasia and polymicrogyria (Warburg et al, ). WARBM can be caused directly by loss of function of RAB18, or indirectly through loss of RAB18 regulators, RAB3GAP or TBC1D20 (Dejgaard and Presley, ). RAB18 is implicated in a wide variety of processes including vesicle trafficking, axonal transport, and synaptic transmission, with major role in autophagy and tethering endoplasmic reticulum (ER) (Dejgaard and Presley, ).…”

Section: Introductionmentioning

confidence: 99%

“…WARBM can be caused directly by loss of function of RAB18, or indirectly through loss of RAB18 regulators, RAB3GAP or TBC1D20 (Dejgaard and Presley, ). RAB18 is implicated in a wide variety of processes including vesicle trafficking, axonal transport, and synaptic transmission, with major role in autophagy and tethering endoplasmic reticulum (ER) (Dejgaard and Presley, ). TBC1D20 and RAS3GAP were proposed to act in a regulatory cycle to promote RAB18 membrane extraction from ER and retargeting to the Golgi, where RAB3GAP/RAB18GEF work to recruit and stabilize it (Handley et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…TBC1D20 and RAS3GAP were proposed to act in a regulatory cycle to promote RAB18 membrane extraction from ER and retargeting to the Golgi, where RAB3GAP/RAB18GEF work to recruit and stabilize it (Handley et al, ). In the absence of functional RAB3GAP or TBC1D20, the level, localization and dynamics of cellular RAB18 are altered (Handley et al, ; Dejgaard and Presley, ). Until now, four disease genes for WARBM, RAB3GAP1 (MIM 602536), RAB3GAP2 (MIM 609275), RAB18 (MIM 602207) and TBC1D20 (MIM 611663), have been identified (Aligianis et al, ; Bem et al, ; Handley et al, ; Liegel et al, ; Imagawa et al, ; Asahina et al, ; Loiudice et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Martsolf syndrome with novel mutation in the TBC1D20 gene in a family from Iran

Hozhabri

Talebi

Mehrjardi

et al. 2020

American J of Med Genetics Pt A

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Warburg Micro syndrome and Martsolf syndrome are phenotypically overlapping autosomal recessive conditions characterized by multiple organ abnormalities involving the ocular, nervous, and endocrine systems. Warburg Micro syndrome, the more severe of the two conditions, is caused by loss of function mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20 genes, whereas Martsolf syndrome has been attributed to less damaging mutations in RAB3GAP1 and RAB3GAP2 genes. We report the clinical description and molecular characterization of a consanguineous Iranian family with two siblings, a male and a female, with dysmorphic features, bilateral congenital cataracts, optic nerve atrophy, congenital glaucoma, mild to moderate intellectual disability, seizures, hypogonadism, and mild osteoporosis. Spastic quadri-

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Rab18: new insights into the function of an essential protein

Cited by 32 publications

References 87 publications

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

RAB6 GTPase is a crucial regulator of the mammary secretory function controlling STAT5 activation

Martsolf syndrome with novel mutation in the TBC1D20 gene in a family from Iran

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