Inositol Polyphosphate Multikinase Signaling: Multifaceted Functions in Health and Disease

Lee, Boah; Park, Seung Ju; Hong, Se-Hoon; Kim, Kyunghan; Kim, Se-Yun

doi:10.14348/molcells.2021.0045

Cited by 22 publications

(18 citation statements)

References 53 publications

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“…Finally, we transfected cells with two different siRNAs targeting inositol polyphosphate multikinase (IPMK), an upstream kinase required for both IP 5 and IP 6 biosynthesis 28 , 29 . We assessed Integrator function using two reporters where the U7snRNA promoter, gene body, and 3′ cleavage site are placed upstream of either GFP or luciferase with the rationale that loss of Integrator function leads to transcriptional readthrough and expression of the downstream open reading frames (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inositol hexakisphosphate is required for Integrator function

et al. 2022

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Integrator is a multi-subunit protein complex associated with RNA polymerase II (Pol II), with critical roles in noncoding RNA 3′-end processing and transcription attenuation of a broad collection of mRNAs. IntS11 is the endonuclease for RNA cleavage, as a part of the IntS4-IntS9-IntS11 Integrator cleavage module (ICM). Here we report a cryo-EM structure of the Drosophila ICM, at 2.74 Å resolution, revealing stable association of an inositol hexakisphosphate (IP6) molecule. The IP6 binding site is located in a highly electropositive pocket at an interface among all three subunits of ICM, 55 Å away from the IntS11 active site and generally conserved in other ICMs. We also confirmed IP6 association with the same site in human ICM. IP6 binding is not detected in ICM samples harboring mutations in this binding site. Such mutations or disruption of IP6 biosynthesis significantly reduced Integrator function in snRNA 3′-end processing and mRNA transcription attenuation. Our structural and functional studies reveal that IP6 is required for Integrator function in Drosophila, humans, and likely other organisms.

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Section: Resultsmentioning

confidence: 99%

Inositol hexakisphosphate is required for Integrator function

et al. 2022

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“…IP3 can be subsequently phosphorylated by inositol kinases yielding several phosphorylated species (e.g. inositol 1,4,5,6 tetrakisphosphate (IP4), inositol 1,3,4,5,6 pentakisphosphate (IP5), inositol 1,2,3,4,5,6 hexakisphosphate (IP6), and 5-diphosphoinositol pentakisphosphate (IP7)) [ 78 , 79 ]. The second cellular source of inositol polyphosphates (IPs) is hydrolysis of membrane phospholipids—a process tightly involved in cellular signal transduction, where IPs act as messenger molecules mediating various processes.…”

Section: Chromatin-regulating Metabolites Originating From Carbohydratesmentioning

confidence: 99%

Unconventional metabolites in chromatin regulation

2022

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Chromatin, the complex of DNA and histone proteins, serves as a main integrator of cellular signals. Increasing evidence links cellular functional to chromatin state. Indeed, different metabolites are emerging as modulators of chromatin function and structure. Alterations in chromatin state are decisive for regulating all aspects of genome function and ultimately have the potential to produce phenotypic changes. Several metabolites such as acetyl-CoA, S-adenosyl methionine (SAM) or adenosine triphosphate (ATP) have now been well characterized as main substrates or cofactors of chromatin modifying enzymes. However, there are other metabolites that can directly interact with chromatin influencing its state or that modulate the properties of chromatin regulatory factors. Also, there is a growing list of atypical enzymatic and non-enzymatic chromatin modifications that originate from different cellular pathways that have not been in the limelight of chromatin research. Here, we summarize different properties and functions of uncommon regulatory molecules originating from intermediate metabolism of lipids, carbohydrates and amino acids. Based on the various modes of action on chromatin and the plethora of putative, so far not described chromatin regulating metabolites, we propose that there are more links between cellular functional state and chromatin regulation to be discovered. We hypothesize that these connections could provide interesting starting points for interfering with cellular epigenetic states at a molecular level.

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“…The soluble inositol poly/pyro-phosphates are involved in many different cellular systems (reviewed by [ 76 , 77 ]). Wu et al showed that Sse1, Hsp26, Ssb1/2 and Hsp104, among many other proteins, bound to affinity columns prepared with 5PP-IP5 or IP6 [ 78 ].…”

Section: Siw14 Curing Of [Psi+] and Inositol Polyphosphatesmentioning

confidence: 99%

Anti-Prion Systems Block Prion Transmission, Attenuate Prion Generation, Cure Most Prions as They Arise and Limit Prion-Induced Pathology in Saccharomyces cerevisiae

Wickner

Edskes

Son

et al. 2022

Biology

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All variants of the yeast prions [PSI+] and [URE3] are detrimental to their hosts, as shown by the dramatic slowing of growth (or even lethality) of a majority, by the rare occurrence in wild isolates of even the mildest variants and by the absence of reproducible benefits of these prions. To deal with the prion problem, the host has evolved an array of anti-prion systems, acting in normal cells (without overproduction or deficiency of any component) to block prion transmission from other cells, to lower the rates of spontaneous prion generation, to cure most prions as they arise and to limit the damage caused by those variants that manage to elude these (necessarily) imperfect defenses. Here we review the properties of prion protein sequence polymorphisms Btn2, Cur1, Hsp104, Upf1,2,3, ribosome-associated chaperones, inositol polyphosphates, Sis1 and Lug1, which are responsible for these anti-prion effects. We recently showed that the combined action of ribosome-associated chaperones, nonsense-mediated decay factors and the Hsp104 disaggregase lower the frequency of [PSI+] appearance as much as 5000-fold. Moreover, while Btn2 and Cur1 are anti-prion factors against [URE3] and an unrelated artificial prion, they promote [PSI+] prion generation and propagation.

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Inositol Polyphosphate Multikinase Signaling: Multifaceted Functions in Health and Disease

Cited by 22 publications

References 53 publications

Inositol hexakisphosphate is required for Integrator function

Inositol hexakisphosphate is required for Integrator function

Unconventional metabolites in chromatin regulation

Anti-Prion Systems Block Prion Transmission, Attenuate Prion Generation, Cure Most Prions as They Arise and Limit Prion-Induced Pathology in Saccharomyces cerevisiae

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