<scp>RAB6</scp> and dynein drive <scp>post‐Golgi</scp> apical transport to prevent neuronal progenitor delamination

Brault, Jean‐Baptiste; Bardin, Sabine; Lampic, Marusa; Carpentieri, Jacopo Amerigo; Coquand, Laure; Penisson, Maxime; Lachuer, Hugo; Victoria, Guiliana Soraya; Baloul, Sarah; Marjou, Fatima El; Boncompain, Gaëlle; Miserey-Lenkei, Stéphanie; Belvindrah, Richard; Fraisier, Vincent; Francis, Fiona; Perez, Franck; Goud, Bruno; Baffet, Alexandre D.

doi:10.15252/embr.202254605

Cited by 21 publications

(12 citation statements)

References 74 publications

(99 reference statements)

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“…Consistent with the phenotypes of our Spast KO/KO mice, SEPT2 and NUDC also have established functions in regulating mitotic spindle architecture and in cytokinesis. Also consistent with the phenotype observed in null germ cells, the dynein–dynactin complex facilitates vesicle transport in multiple somatic cell types (reviewed by Liu, 2017 ; Reck-Peterson et al, 2018 ), including post-Golgi transport in mouse radial glial cells ( Brault et al, 2022 ), and SEPT2 has been shown to have roles in vesicle transport in Madin–Darby canine kidney (MDCK) cells ( Spiliotis et al, 2008 ). Of direct relevance to the mechanism of action of spastin in severing polyglutamylated tubulin and the aberrant transport of Golgi-derived vesicles during acrosome formation herein, published data suggest that SEPT2-based filaments facilitate post-Golgi vesicle transport along polyglutamylated microtubules ( Spiliotis et al, 2008 ), raising the possibility that SEPT2 has similar roles in male germ cells.…”

Section: Resultsmentioning

confidence: 61%

Spastin is an essential regulator of male meiosis, acrosome formation, manchette structure and nuclear integrity

et al. 2023

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The development and function of male gametes is critically dependent on a dynamic microtubule network, yet how this is regulated remains poorly understood. We have recently shown that microtubule severing, via the action of the meiotic AAA ATPase protein clade, plays a critical role in this process. Here, we sought to elucidate the roles of spastin, an as yet unexplored member of this clade in spermatogenesis. Using a SpastKO/KO mouse model, we reveal that spastin loss resulted in a complete loss of functional germ cells. Spastin plays a critical role in the assembly and function of the male meiotic spindle. Consistent with meiotic failure, round spermatid nuclei were enlarged, indicating aneuploidy, but were still able to enter spermiogenesis. During spermiogenesis, we observed extreme abnormalities in manchette structure, acrosome biogenesis, and commonly, a catastrophic loss of nuclear integrity. This work defines a novel and essential role for spastin in regulating microtubule dynamics during spermatogenesis and is of potential relevance to patients carrying spastin variants and the medically assisted reproductive technology industry.

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Section: Resultsmentioning

confidence: 61%

Spastin is an essential regulator of male meiosis, acrosome formation, manchette structure and nuclear integrity

et al. 2023

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“…The results indeed indicated that Rab4A-Q72L mutant expression greatly increases KDELR1 expression at the PM, whereas S27N mutant failed to do so ( Figure 5 A), as shown by the surface biotinylation experiments. It is well known that Rab6A and Rab8A are small GTPases involved in the transport of post-Golgi vesicles [ 37 , 38 , 39 , 40 ]. We also tested whether the surface level of KDELR1-mCherry was changed after overexpressing Rab6A-Q72L/T27N and Rab8A-Q67L/T22N mutant pairs.…”

Section: Resultsmentioning

confidence: 99%

KDEL Receptor Trafficking to the Plasma Membrane Is Regulated by ACBD3 and Rab4A-GTP

Tan

Zhu

et al. 2023

Cells

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KDEL receptor-1 maintains homeostasis in the early secretory pathway by capturing and retrieving ER chaperones to the ER during heavy secretory activity. Unexpectedly, a fraction of the receptor is also known to reside in the plasma membrane (PM), although it is largely unknown exactly how the KDEL receptor gets exported from the Golgi and travels to the PM. We have previously shown that a Golgi scaffolding protein (ACBD3) facilitates KDEL receptor localization at the Golgi via the regulating cargo wave-induced cAMP/PKA-dependent signaling pathway. Upon endocytosis, surface-expressed KDEL receptor undergoes highly complex itineraries through the Golgi and the endo-lysosomal compartments, where the endocytosed receptor utilizes Rab14A- and Rab11A-positive recycling endosomes and clathrin-decorated tubulovesicular carriers. In this study, we sought to investigate the mechanism through which the KDEL receptor gets exported from the Golgi en route to the PM. We report here that ACBD3 depletion results in greatly increased trafficking of KDEL receptor to the PM via Rab4A-positive tubular carriers emanating from the Golgi. Expression of constitutively activated Rab4A mutant (Q72L) increases the surface expression of KDEL receptor up to 2~3-fold, whereas Rab4A knockdown or the expression of GDP-locked Rab4A mutant (S27N) inhibits KDEL receptor targeting of the PM. Importantly, KDELR trafficking from the Golgi to the PM is independent of PKA- and Src kinase-mediated mechanisms. Taken together, these results reveal that ACBD3 and Rab4A play a key role in regulating KDEL receptor trafficking to the cell surface.

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“…The growth inhibitory effect of statins in PPARGC1A silenced cells can be rescued by mevalonate or GGPP supplementation, or combinatorial expression of wild-type alleles of RAB6B and RAB27A. RAB proteins are key regulators of endosomal trafficking and linked to localization of proteins to plasma membrane 32 – 35 . RAB proteins require prenylation of the C-terminal CAAX using GGPP – a covalently attached lipid-moiety that allows membrane insertion 36 , 37 .…”

Section: Discussionmentioning

confidence: 99%

Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas

Liang

Luo

et al. 2023

Nat Commun

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While targeted treatment against BRAF(V600E) improve survival for melanoma patients, many will see their cancer recur. Here we provide data indicating that epigenetic suppression of PGC1α defines an aggressive subset of chronic BRAF-inhibitor treated melanomas. A metabolism-centered pharmacological screen further identifies statins (HMGCR inhibitors) as a collateral vulnerability within PGC1α-suppressed BRAF-inhibitor resistant melanomas. Lower PGC1α levels mechanistically causes reduced RAB6B and RAB27A expression, whereby their combined re-expression reverses statin vulnerability. BRAF-inhibitor resistant cells with reduced PGC1α have increased integrin-FAK signaling and improved extracellular matrix detached survival cues that helps explain their increased metastatic ability. Statin treatment blocks cell growth by lowering RAB6B and RAB27A prenylation that reduces their membrane association and affects integrin localization and downstream signaling required for growth. These results suggest that chronic adaptation to BRAF-targeted treatments drive novel collateral metabolic vulnerabilities, and that HMGCR inhibitors may offer a strategy to treat melanomas recurring with suppressed PGC1α expression.

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RAB6 and dynein drive post‐Golgi apical transport to prevent neuronal progenitor delamination

Cited by 21 publications

References 74 publications

Spastin is an essential regulator of male meiosis, acrosome formation, manchette structure and nuclear integrity

Spastin is an essential regulator of male meiosis, acrosome formation, manchette structure and nuclear integrity

KDEL Receptor Trafficking to the Plasma Membrane Is Regulated by ACBD3 and Rab4A-GTP

Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas

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