Intimate connections: Inositol pyrophosphates at the interface of metabolic regulation and cell signaling

Shears, Stephen B.

doi:10.1002/jcp.26017

Cited by 104 publications

(169 citation statements)

References 111 publications

(223 reference statements)

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“…The immediate target(s) of IP8 in eliciting the effects we describe here are as yet unknown. Two distinct themes have been invoked previously to account for IPP effects, whereby IPPs either: (i) bind to target proteins and allosterically enhance or inhibit their functions; or (ii) serve as phosphate donors for transfer of an IPP bphosphate to a previously mono-phosphorylated protein target leading to a covalent pyrophosphate modification of the target (34)(35)(36)(37). Potential mechanisms for IP8 to promote 3'processing/termination include: (i) allosteric binding or covalent modification of the processing/termination machinery so as to enhance its action on elongating Pol2; (ii) allosteric interaction with, or covalent modification of Pol2 to make it more responsive to the processing/termination machinery.…”

Section: Discussionmentioning

confidence: 99%

Inositol pyrophosphates impact phosphate homeostasis via modulation of RNA 3’ processing and transcription termination

Sánchez

Garg

Schwer

et al. 2019

Preprint

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Fission yeast phosphate acquisition genes pho1, pho84, and tgp1 are repressed in phosphate-rich medium by transcription of upstream lncRNAs. Here we show that phosphate homeostasis is subject to metabolite control by inositol pyrophosphates (IPPs), exerted through the 3'-processing/termination machinery and the Pol2 CTD code. Increasing IP8 (via Asp1 IPP pyrophosphatase mutation) de-represses the PHO regulon and leads to precocious termination of prt lncRNA synthesis. pho1 de-repression by IP8 depends on cleavage-polyadenylation factor (CPF) subunits, termination factor Rhn1, and the Thr4 letter of the CTD code. pho1 de-repression by mutation of the Ser7 CTD letter depends on IP8. Simultaneous inactivation of the Asp1 and Aps1 IPP pyrophosphatases is lethal, but this lethality is suppressed by mutations of CPF subunits Ppn1, Swd22, Ssu72, and Ctf1 and CTD mutation T4A. Failure to synthesize IP8 (via Asp1 IPP kinase mutation) results in pho1 hyper-repression. Synthetic lethality of asp1∆ with Ppn1, Swd22, and Ssu72 mutations argues that IP8 plays an important role in essential 3'processing/termination events, albeit in a manner genetically redundant to CPF. Transcriptional profiling delineates an IPP-responsive regulon composed of genes overexpressed when IP8 levels are increased. Our results establish a novel role for IPPs in cell physiology.

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Section: Discussionmentioning

confidence: 99%

Inositol pyrophosphates impact phosphate homeostasis via modulation of RNA 3’ processing and transcription termination

Sánchez

Garg

Schwer

et al. 2019

Preprint

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“…We have previously shown that these domains act as cellular receptors for inositol pyrophosphate (PP-InsP) signaling molecules (Wild et al, 2016). PP-InsPs are composed of a fully phosphorylated inositol ring containing one or two pyrophosphate moieties (Shears, 2018). PP-InsPs bind to a basic surface cluster highly conserved among SPX domains to regulate divers biochemical and cellular processes in fungi, plants and animals.…”

Section: Introductionmentioning

confidence: 99%

Two bifunctional inositol pyrophosphate kinases/phosphatases control plant phosphate homeostasis

Zhu

Lau

Harmel

et al. 2018

Preprint

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Many eukaryotic proteins regulating phosphate (Pi) homeostasis contain SPX domains. We have previously shown that these domains act as cellular receptors for inositol pyrophosphate (PP-InsP) signaling molecules, suggesting that PP-InsPs may regulate Pi homeostasis. Here we report that simultaneous deletion of two diphosphoinositol pentakisphosphate kinases VIH1 and 2 in Arabidopsis impairs plant growth and leads to constitutive Pi starvation responses. We demonstrate that VIH1 and VIH2 are bifunctional cytosolic enzymes able to generate and break-down PP-InsPs. Point-mutants targeting the kinase and phosphatase active sites have opposing effects on plant Pi content and Pi starvation responses, while VIH1 and VIH2 protein levels remain constant in different Pi growth conditions. Enzymatic assays reveal that ATP-Mg 2+ substrate levels can shift the relative kinase and phosphatase activities of fulllength diphosphoinositol pentakisphosphate kinases. Deletion of phosphate starvation response transcription factors rescues vih1 vih2 mutant phenotypes, placing diphosphoinositol pentakisphosphate kinases and PP-InsPs in plant phosphate signal transduction cascades. We propose that VIH1 and VIH2 relay changes in cellular ATP concentration to changes in PP-InsP levels, allowing plants to maintain cellular Pi concentrations constant and to trigger Pi starvation responses.

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“…Inositol pyrophosphates are derivatives of myo-inositol characterized by the presence of one or more diphosphates in addition to monophosphates around the inositol ring (1). These small molecules are found in all eukaryotic cells, and are involved in the regulation of many cellular processes, including energy and phosphate metabolism, DNA repair, ribosome biogenesis, vesicle trafficking and insulin secretion (1)(2)(3)(4)(5). In mammals, the most abundant inositol pyrophosphate is 5-diphosphoinositol pentakisphosphate (5-PP-IP5 or 5-IP7), which is synthesized from inositol hexakisphosphate (IP6) by IP6 kinases.…”

Section: Introductionmentioning

confidence: 99%

A pyro-phosphodegron controls MYC polyubiquitination to regulate cell survival

Lolla

Shah

Unnikannan

et al. 2020

Preprint

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The transcription factor MYC regulates cell survival and growth, and its level is tightly controlled in normal cells. Here, we report that serine pyrophosphorylationan enigmatic posttranslational modification triggered by inositol pyrophosphate signaling moleculescontrols MYC levels via regulated protein degradation. We find that endogenous MYC is stabilized and less polyubiquitinated in cells with reduced inositol pyrophosphates. We show that the inositol pyrophosphate 5-IP7 transfers its high-energy beta phosphate moiety to pre-phosphorylated serine residues in the central PEST domain of MYC. Pyrophosphorylation of MYC promotes its interaction with the E3 ubiquitin ligase FBW7, thereby enhancing MYC polyubiquitination and degradation. FBW7 can bind directly to the PEST domain of MYC in a pyrophosphorylationdependent manner. A stabilized, pyrophosphorylation-deficient form of MYC increases cell death during growth stress in untransformed cells, and promotes cell proliferation in response to mitogens. Thus, control of MYC stability through a novel pyro-phosphodegron provides unexpected insight into the regulation of cell survival in response to environmental cues.

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Intimate connections: Inositol pyrophosphates at the interface of metabolic regulation and cell signaling

Cited by 104 publications

References 111 publications

Inositol pyrophosphates impact phosphate homeostasis via modulation of RNA 3’ processing and transcription termination

Inositol pyrophosphates impact phosphate homeostasis via modulation of RNA 3’ processing and transcription termination

Two bifunctional inositol pyrophosphate kinases/phosphatases control plant phosphate homeostasis

A pyro-phosphodegron controls MYC polyubiquitination to regulate cell survival

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