Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response

Pulloor, Niyas Kudukkil; Nair, Sajith; Kostic, Aleksandar D.; Bist, Pradeep; Weaver, Jeremy D.; Riley, Andrew M.; Tyagi, Richa; Uchil, Pradeep D.; York, John D.; Snyder, Solomon H.; García‐Sastre, Adolfo; Potter, Barry V. L.; Lin, Rongtuan; Shears, Stephen B.; Xavier, Ramnik J.; Krishnan, Manoj N.

doi:10.1371/journal.ppat.1003981

Cited by 71 publications

(76 citation statements)

References 72 publications

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“…It has been reported that 1-IP7 promotes the phosphorylation of IRF3, as does IP8, albeit less potently (23). In this study, we find that 5-IP7 promotes FAK phosphorylation.…”

Section: Discussionsupporting

confidence: 51%

Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via α-actinin and focal adhesion kinase

Cheng

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Inositol hexakisphosphate kinase 1 (IP6K1), which generates 5-diphosphoinositol pentakisphosphate (5-IP7), physiologically mediates numerous functions. We report that IP6K1 deletion leads to brain malformation and abnormalities of neuronal migration. IP6K1 physiologically associates with α-actinin and localizes to focal adhesions. IP6K1 deletion disrupts α-actinin's intracellular localization and function. The IP6K1 deleted cells display substantial decreases of stress fiber formation and impaired cell migration and spreading. Regulation of α-actinin by IP6K1 requires its kinase activity. Deletion of IP6K1 abolishes α-actinin tyrosine phosphorylation, which is known to be regulated by focal adhesion kinase (FAK). FAK phosphorylation is substantially decreased in IP6K1 deleted cells. 5-IP7, a product of IP6K1, promotes FAK autophosphorylation. Pharmacologic inhibition of IP6K by TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] recapitulates the phenotype of IP6K1 deletion. These findings establish that IP6K1 physiologically regulates neuronal migration by binding to α-actinin and influencing phosphorylation of both FAK and α-actinin through its product 5-IP7.IP6K | inositol pyrophosphate | brain malformation | actinin | FAK

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“…It has been reported that 1-IP7 promotes the phosphorylation of IRF3, as does IP8, albeit less potently (23). In this study, we find that 5-IP7 promotes FAK phosphorylation.…”

Section: Discussionsupporting

confidence: 51%

Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via α-actinin and focal adhesion kinase

Cheng

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Another example of transcription regulation by 1-IP 7 was seen in the mammalian innate immune response. 122 1-IP 7 but not 5-IP 7 increased phosphorylation and activation of the transcription factor IRF3, which is responsible for production of the cytokine IFNβ upon viral infection. Interestingly, a non-hydrolysable analogue of 1-IP 7 could not recapitulate this effect, suggesting that 1-IP 7 -mediated specific pyrophosphorylation may be involved in this pathway.…”

Section: Transcriptionmentioning

confidence: 94%

Inositol Pyrophosphates: Energetic, Omnipresent and Versatile Signalling Molecules

et al. 2017

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| Inositol pyrophosphates (PP-IPs) are a class of energy-rich signalling molecules found in all eukaryotic cells. These are derivatives of inositol that contain one or more diphosphate (or pyrophosphate) groups in addition to monophosphates. The more abundant and best studied PP-IPs are diphosphoinositol pentakisphosphate (IP 7 ) and bis-diphosphoinositol tetrakisphosphate (IP 8 ). These molecules can influence protein function by two mechanisms: binding and pyrophosphorylation. The former involves the specific interaction of a particular inositol pyrophosphate with a binding site on a protein, while the latter is a unique attribute of inositol pyrophosphates, wherein the β-phosphate moiety is transferred from a PP-IP to a pre-phosphorylated serine residue in a protein to generate pyrophosphoserine. Both these events can result in changes in the target protein's activity, localisation or its interaction with other partners. As a consequence of their ubiquitous presence in all eukaryotic organisms and all cell types examined till date, and their ability to modify protein function, PP-IPs have been found to participate in a wide range of metabolic, developmental, and signalling pathways.This review highlights many of the known functions of PP-IPs in the context of their temporal and spatial distribution in eukaryotic cells. The pathway of synthesis of inositol polyphosphates has been characterized in yeast, slime moulds, plants and animals. The simplest anabolic pathway, characterized in the yeast Saccharomyces cerevisiae (Fig. 1) (Fig. 1). Interestingly, the PPIP5Ks also possess a phosphatase domain which selectively cleaves the 1-position β-phosphate of 1-IP 7 and IP 8 , thus targeting the products of the kinase domain.35, 36 A recent study identified another yeast phosphatase, Siw14, that specifically targets the 5-position β-phosphate of PP-IPs 37 (Fig. 1). As PP-IPs are found in all eukaryotic organisms, they display many conserved and divergent 2, 131 Siw14, an inositol pyrophosphate phosphatase in yeast, preferentially cleaves the C5 β-phosphate on PP-IPs. 37 The yeast enzymes are depicted in purple, and mammalian enzymes are depicted in green and are bracketed. The undetermined inositol pyrophosphate structure is represented with an interrogation mark. Myoinositol contains five equatorial (parallel to the axis) and one axial (perpendicular to the axis) hydroxyl groups. Carbon atoms on the myo-inositol ring are numbered on the structures of PI(4,5)P 2 and IP 6 .

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“…Again, this enzymatic activity is highly substrate specific, as in vitro analysis showed that the C-terminal Asp1 domain hydrolyzes the diphosphate exclusively at position 1 of the inositol ring (17). Vip1 members regulate a wide variety of eukaryotic processes ranging from the human antiviral response to plant defense mechanisms against insects (10,11,(18)(19)(20). In fission yeast, the Vip1 member Asp1 regulates the dimorphic switch, which is a dramatic morphological alteration in response to changing environmental conditions (21).…”

mentioning

confidence: 99%

Inositol Pyrophosphate Kinase Asp1 Modulates Chromosome Segregation Fidelity and Spindle Function in Schizosaccharomyces pombe

Topolski

Jakopec

Kuenzel

et al. 2016

Molecular and Cellular Biology

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Chromosome transmission fidelity during mitosis is of critical importance for the fitness of an organism, as mistakes will lead to aneuploidy, which has a causative role in numerous severe diseases. Proper segregation of chromosomes depends on interdependent processes at the microtubule-kinetochore interface and the spindle assembly checkpoint. Here we report the discovery of a new element essential for chromosome transmission fidelity that implicates inositol pyrophosphates (IPPs) as playing a key role in this process. The protein is Asp1, the Schizosaccharomyces pombe member of the highly conserved Vip1 family. Vip1 enzymes are bifunctional: they consist of an IPP-generating kinase domain and a pyrophosphatase domain that uses such IPPs as substrates. We show that Asp1 kinase function is required for bipolar spindle formation. The absence of Asp1-generated IPPs resulted in errors in sister chromatid biorientation, a prolonged checkpoint-controlled delay of anaphase onset, and chromosome missegregation. Remarkably, expression of Asp1 variants that generated higher-than-wild-type levels of IPPs led to a fasterthan-wild-type entry into anaphase A without an increase in chromosome missegregation. In fact, the chromosome transmission fidelity of a nonessential chromosome was enhanced with increased cellular IPPs. Thus, we identified an element that optimized the wild-type chromosome transmission process. In eukaryotes, the faithful transmission of genetic information from one generation to the next is tightly controlled. Genome instability generally has a strong negative impact on the fitness of an organism. Decreased chromosome segregation fidelity during cell division will give rise to cell progeny which have lost or gained chromosomes. Aneuploidy is a distinguishing feature of many types of cancer and neurological diseases and has been implicated as an important factor in the aging process (1, 2). It is a poorly understood paradox that genome plasticity can also be advantageous for the propagation of cells or an organism. Aneuploid tumor cells have a proliferative advantage, and large-scale chromosome changes are a common feature of human-pathogenic fungi such as Candida. In the latter case, these alterations facilitate an adaption to the environment resulting in increased survival (3).Chromosome segregation is a precise process: in model yeasts such as the fission yeast Schizosaccharomyces pombe where in vivo chromosome loss rates can be determined easily, it is approximately 0.01% (reviewed in reference 4). Chromosome transmission fidelity depends on the formation and function of the bipolar spindle, the multicomponent kinetochore complex assembled on centromeric chromatin, and the correct connections between these two structures. Biorientation of sister chromatids requires the binding of plus ends of spindle microtubules (MTs) to attachment sites on the kinetochore in such a way that sisters are bound to MTs polymerized from opposing spindle poles. Incorrect attachments are common and are corrected by the Aur...

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Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response

Cited by 71 publications

References 72 publications

Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via α-actinin and focal adhesion kinase

Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via α-actinin and focal adhesion kinase

Inositol Pyrophosphates: Energetic, Omnipresent and Versatile Signalling Molecules

Inositol Pyrophosphate Kinase Asp1 Modulates Chromosome Segregation Fidelity and Spindle Function in Schizosaccharomyces pombe

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