Septin-mediated RhoA activation engages the exocyst complex to recruit the cilium transition zone

Safavian, Darya; Kim, Moshe S.; Xie, Hui; El-Zeiry, Maha; Palander, Oliva; Dai, Lu; Collins, Richard F.; Froese, Carol D.; Shannon, Rachel; Nagata, Koh‐ichi; Trimble, William S.

doi:10.1083/jcb.201911062

Cited by 4 publications

(8 citation statements)

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“…Septins also regulate RhoA activity and actin polymerization facilitating trafficking of ciliary cargo proteins ( 13 ). For example, SEPTIN9 enhances the activity of ARHGEF18, which in turn activates RhoA ( 115 ). In this context, activated RhoA is required for the assembly of the complete exocyst complex ( 116 ), which orchestrates transport of post-Golgi vesicles containing transition zone proteins of the NPHP and MKS complexes ( 115 , 117 ).…”

Section: Molecular Determinants Of Actin Regulation At the Primary Ci...mentioning

confidence: 99%

Primary cilia and actin regulatory pathways in renal ciliopathies

Kalot,

Sentell,

Kitzler

et al. 2024

Front. Nephrol.

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Ciliopathies are a group of rare genetic disorders caused by defects to the structure or function of the primary cilium. They often affect multiple organs, leading to brain malformations, congenital heart defects, and anomalies of the retina or skeletal system. Kidney abnormalities are among the most frequent ciliopathic phenotypes manifesting as smaller, dysplastic, and cystic kidneys that are often accompanied by renal fibrosis. Many renal ciliopathies cause chronic kidney disease and often progress to end-stage renal disease, necessitating replacing therapies. There are more than 35 known ciliopathies; each is a rare hereditary condition, yet collectively they account for a significant proportion of chronic kidney disease worldwide. The primary cilium is a tiny microtubule-based organelle at the apex of almost all vertebrate cells. It serves as a “cellular antenna” surveying environment outside the cell and transducing this information inside the cell to trigger multiple signaling responses crucial for tissue morphogenesis and homeostasis. Hundreds of proteins and unique cellular mechanisms are involved in cilia formation. Recent evidence suggests that actin remodeling and regulation at the base of the primary cilium strongly impacts ciliogenesis. In this review, we provide an overview of the structure and function of the primary cilium, focusing on the role of actin cytoskeleton and its regulators in ciliogenesis. We then describe the key clinical, genetic, and molecular aspects of renal ciliopathies. We highlight what is known about actin regulation in the pathogenesis of these diseases with the aim to consider these recent molecular findings as potential therapeutic targets for renal ciliopathies.

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Section: Molecular Determinants Of Actin Regulation At the Primary Ci...mentioning

confidence: 99%

Primary cilia and actin regulatory pathways in renal ciliopathies

Kalot,

Sentell,

Kitzler

et al. 2024

Front. Nephrol.

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show abstract

“…All in all this reveals that ciliary septin function requires septin basic building blocks (SEPT7), relies on octamers (SEPT9) and suggests that septins form filaments. Yet, septin-related extra ciliary functions for example in vesicle transport (10,18,19) might also influence cilia number and length. However, these results corroborate previous studies that have assigned an important role in ciliogenesis to the septin cytoskeleton (5)(6)(7)20).…”

Section: Septins Localize To Ciliamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Septin-dependent localization and interactions were observed for several transition zone proteins like Cc2d2a, B9D1, Tmem231 (8) or DZIP1L (9). Recently, it was shown that SEPT9 regulates the recruitment of transition zone proteins on Golgi-derived vesicles by activating the exocyst via the ARHGEF18 and RhoA (10). Most studies concur that inhibition of septins by any means results in less formation of cilia (5, 6, 10).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, it was shown that SEPT9 regulates the recruitment of transition zone proteins on Golgi-derived vesicles by activating the exocyst via the ARHGEF18 and RhoA (10). Most studies concur that inhibition of septins by any means results in less formation of cilia (5, 6, 10). While steadily important functions of septins at cilia emerge, the regulation of septin accumulation at cilia remains less intensively studied.…”

Section: Introductionmentioning

confidence: 99%

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Borg3 controls septin recruitment for primary cilia formation

Schampera,

Lehmann,

Meléndez

et al. 2024

Preprint

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Septin GTPases polymerize into higher-order structures as a part of the cytoskeleton and are involved in vital cellular functions. Among these, they play a role in the formation of primary cilia. However, the regulation of septin assembly in the confined ciliary compartment has not been studied in detail. Here we show, that Borg3 also known as Cdc42EP5, a regulator of septin assembly is involved in the formation of cilia. Borg3 accumulation in cilia is facilitated by switching the Rho-GTPase Cdc42 between an inactive and active state at the base of the primary cilium. Knock out of Borg3 as well as dysregulation of Cdc42 results in reduced septin localization to the primary cilium and reduced formation of cilia.

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Septins function in exocytosis via physical interactions with the exocyst complex in fission yeast cytokinesis

Singh,

Liu,

Zhu

et al. 2024

Preprint

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Septins can function as scaffolds for protein recruitment, membrane-bound diffusion barriers, or membrane curvature sensors. Septins are important for cytokinesis, but their exact roles are still obscure. In fission yeast, four septins (Spn1 to Spn4) accumulate at the rim of the division plane as rings. The octameric exocyst complex, which tethers exocytic vesicles to the plasma membrane, exhibits a similar localization and is essential for plasma membrane deposition during cytokinesis. Without septins, the exocyst spreads across the division plane but absent from the rim during septum formation. These results suggest that septins and the exocyst physically interact for proper localization. Indeed, we predicted six pairs of direct interactions between septin and exocyst subunits by AlphaFold2 ColabFold, most of them are confirmed by co-immunoprecipitation and yeast two-hybrid assays. Exocyst mislocalization results in mistargeting of secretory vesicles and their cargos, which leads to cell-separation delay in septin mutants. Our results indicate that septins guide the targeting of exocyst complex on the plasma membrane for vesicle tethering during cytokinesis through direct physical interactions.

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Septin-mediated RhoA activation engages the exocyst complex to recruit the cilium transition zone

Cited by 4 publications

References 50 publications

Primary cilia and actin regulatory pathways in renal ciliopathies

Primary cilia and actin regulatory pathways in renal ciliopathies

Borg3 controls septin recruitment for primary cilia formation

Septins function in exocytosis via physical interactions with the exocyst complex in fission yeast cytokinesis

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