INPP5E regulates phosphoinositide-dependent cilia transition zone function

Dyson, Jennifer M; Conduit, Sarah E; Feeney, Sandra J.; Hakim, Sandra; DiTommaso, Tia; Fulcher, Alex J.; Sriratana, Absorn; Ramm, Georg; Horan, Kristy; Gurung, Rajendra; Wicking, Carol; Smyth, Ian; Mitchell, Christina A.

doi:10.1083/jcb.201511055

Cited by 105 publications

(194 citation statements)

References 87 publications

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“…Given that INPP5E is an inositol 5polyphosphatase, it could conceivably control second messenger phosphatidylinositol (PI) signalling at the plasma membrane as it does within the cilium where it maintains a high concentration of PI-4-phosphate (PI(4)P) relative to PI(4,5)P 2 , an attribute linked to ciliary stability 61,62 . Indeed, another second messenger, PI(5)P is induced by Newcastle disease virus infection and poly(I:C), and can act as an innate immune effector promoting type I IFN production through the TBK1-IRF3 signalling axis 63 .…”

Section: Discussionmentioning

confidence: 99%

Induction of an alternative 5’ leader enhances translation of Inpp5e and resistance to oncolytic virus infection

Hoang

Jia

et al. 2019

Preprint

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Residual cell-intrinsic innate immunity in cancer cells hampers infection with oncolytic viruses. mRNA translation is an important component of innate immunity, yet the targeted cellular mRNAs remain illdefined. We characterized the translatome of resistant murine "4T1" breast cancer cells infected with three of the most clinically advanced oncolytic viruses: Herpes Simplex virus 1, Reovirus and Vaccinia virus. Common among all three infections were translationally derepressed mRNAs involved in ciliary homeostasis including Inpp5e, encoding an inositol 5-phosphatase that modifies lipid second messenger signalling. Translationally repressed in the uninfected condition, viral infection induced expression of an Inpp5e mRNA variant that lacks repressive upstream open reading frames (uORFs) within its 5' leader and is consequently efficiently translated. Furthermore, we show that INPP5E contributes to antiviral immunity by altering virus attachment. These findings uncover a role for translational control through alternative 5' leader expression and assign ciliary proteins such as INPP5E to the cellular antiviral response.

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Section: Discussionmentioning

confidence: 99%

Induction of an alternative 5’ leader enhances translation of Inpp5e and resistance to oncolytic virus infection

Hoang

Jia

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…These data raise the possibility that transition zone C2 domains instead function to facilitate protein-protein interactions. Adding to the complexity, beyond the transition zone affecting the distribution of phosphoinositides, INPP5E and phosphoinositides may reciprocally influence the composition of the transition zone [130]. Once established within cilia, phosphoinositides help control the distribution of ciliary proteins.…”

Section: Phosphoinositide Compartmentalization and Consequences Of Abmentioning

confidence: 99%

“…Similar to genes encoding several transition zone components, mutations in human INPP5E are a cause of Joubert syndrome, and knockout of mouse Inpp5e results in phenotypes characteristic of ciliopathies, including cystic kidneys and polydactyly [130,150,151]. It will be interesting to assess whether, beyond phosphoinositides, additional ciliary lipids participate in ciliary signaling and the pathogenesis of ciliopathies.…”

Section: Phosphoinositide Compartmentalization and Consequences Of Abmentioning

confidence: 99%

How the Ciliary Membrane Is Organized Inside-Out to Communicate Outside-In

2018

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Cilia, organelles that move to execute functions like fertilization and signal to execute functions like photoreception and embryonic patterning, are composed of a core of nine-fold doublet microtubules overlain by a membrane. Distinct types of cilia display distinct membrane morphologies, ranging from simple domed cylinders to the highly ornate invaginations and membrane disks of photoreceptor outer segments. Critical for the ability of cilia to signal, both the protein and the lipid compositions of ciliary membranes are different from those of other cellular membranes. This specialization presents a unique challenge for the cell as, unlike membrane-bounded organelles, the ciliary membrane is contiguous with the surrounding plasma membrane. This distinct ciliary membrane is generated in concert with multiple membrane remodeling events that comprise the process of ciliogenesis. Once the cilium is formed, control of ciliary membrane composition relies on discrete molecular machines, including a barrier to membrane proteins entering the cilium at a specialized region of the base of the cilium called the transition zone and a trafficking adaptor that controls G protein-coupled receptor (GPCR) localization to the cilium called the BBSome. The ciliary membrane can be further remodeled by the removal of membrane proteins by the release of ciliary extracellular vesicles that may function in intercellular communication, removal of unneeded proteins or ciliary disassembly. Here, we review the structures and transport mechanisms that control ciliary membrane composition, and discuss how membrane specialization enables the cilium to function as the antenna of the cell.

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“…Rhodopsin, 5HT6; Goetz & Anderson 2010;Kathem et al, 2014;McIntyre et al, 2016;Hilgendorf et al, 2016). The ciliary membrane also has a specialised lipid composition that includes specific phosphoinositides essential for normal ciliary structure and function (Jacoby et al, 2009;Chávez et al, 2015;Garcia-Gonzalo et al, 2015;Dyson et al, 2017). The importance of the ciliary membrane for signalling is highlighted by the Shh pathway, wherein Shh activation causes transmembrane Ptch1 to exit the cilium, concomitant with the ciliary entry of the downstream pathway activator, Smo (Corbit et al, 2005;Rohatgi et al, 2007;Milenkovic et al, 2009;Schou et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Endosome maturation factors Rabenosyn‐5/VPS45 and caveolin‐1 regulate ciliary membrane and polycystin‐2 homeostasis

2018

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Primary cilium structure and function relies on control of ciliary membrane homeostasis, regulated by membrane trafficking processes that deliver and retrieve ciliary components at the periciliary membrane. However, the molecular mechanisms controlling ciliary membrane establishment and maintenance, especially in relation to endocytosis, remain poorly understood. Here, using , we describe closely linked functions for early endosome (EE) maturation factors RABS-5 (Rabenosyn-5) and VPS-45 (VPS45) in regulating cilium length and morphology, ciliary and periciliary membrane volume, and ciliary signalling-related sensory behaviour. We demonstrate that RABS-5 and VPS-45 control periciliary vesicle number and levels of select EE/endocytic markers (WDFY-2, CAV-1) and the ciliopathy membrane receptor PKD-2 (polycystin-2). Moreover, we show that CAV-1 (caveolin-1) also controls PKD-2 ciliary levels and associated sensory behaviour. These data link RABS-5 and VPS-45 ciliary functions to the processing of periciliary-derived endocytic vesicles and regulation of ciliary membrane homeostasis. Our findings also provide insight into the regulation of PKD-2 ciliary levels via integrated endosomal sorting and CAV-1-mediated endocytosis.

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INPP5E regulates phosphoinositide-dependent cilia transition zone function

Cited by 105 publications

References 87 publications

Induction of an alternative 5’ leader enhances translation of Inpp5e and resistance to oncolytic virus infection

Induction of an alternative 5’ leader enhances translation of Inpp5e and resistance to oncolytic virus infection

How the Ciliary Membrane Is Organized Inside-Out to Communicate Outside-In

Endosome maturation factors Rabenosyn‐5/VPS45 and caveolin‐1 regulate ciliary membrane and polycystin‐2 homeostasis

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