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Summary Kernel row number (KRN) is a major yield related trait for maize (Zea mays L.) and is also a major goal of breeders, as it can increase the number of kernels per plant. Thus, identifying new genetic factors involving in KRN formation may accelerate improving yield‐related traits genetically. We herein describe a new kernel number‐related gene (KRN5b) identified from KRN QTL qKRN5b and encoding an inositol polyphosphate 5‐phosphatase (5PTase). KRN5b has phosphatase activity towards PI(4,5)P2, PI(3,4,5)P3, and Ins(1,4,5)P3 in vitro. Knocking out KRN5b caused accumulation of PI(4,5)P2 and Ins(1,4,5)P3, resulting in disordered kernel rows and a decrease in the number of kernels and tassel branches. The introgression of the allele with higher expression abundance into different inbred lines could increase the ear weight of the inbred lines and the corresponding hybrids by 10.1%–12.2% via increasing KRN, with no adverse effects on other agronomic traits. Further analyses showed that KRN5b regulates inflorescence development through affecting the synthesis and distribution of hormones. Together, KRN5b contributes to spikelet pair meristem development through inositol phosphate and phosphatidylinositols, making it a selecting target for yield improvement.

The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is hyperactivated in ~70% of breast cancers. Class I PI3K generates PtdIns(3,4,5)P3 at the plasma membrane in response to growth factor stimulation, leading to AKT activation to drive cell proliferation, survival and migration. PTEN negatively regulates PI3K/AKT signalling by dephosphorylating PtdIns(3,4,5)P3 to form PtdIns(4,5)P2. PtdIns(3,4,5)P3 can also be hydrolysed by the inositol polyphosphate 5-phosphatases (5-phosphatases) to produce PtdIns(3,4)P2. Interestingly, while PTEN is a bona fide tumour suppressor and is frequently mutated/lost in breast cancer, 5-phosphatases such as PIPP, SHIP2 and SYNJ2, have demonstrated more diverse roles in regulating mammary tumourigenesis. Reduced PIPP expression is associated with triple negative breast cancers and reduced relapse-free and overall survival. Although PIPP depletion enhances AKT phosphorylation and supports tumour growth, this also inhibits cell migration and metastasis in vivo, in a breast cancer oncogene-driven murine model. Paradoxically, SHIP2 and SYNJ2 are increased in primary breast tumours, which correlates with invasive disease and reduced survival. SHIP2 or SYNJ2 overexpression promotes breast tumourigenesis via AKT-dependent and independent mechanisms. This review will discuss how PTEN, PIPP, SHIP2 and SYNJ2 distinctly regulate multiple functional targets, and the mechanisms by which dysregulation of these distinct phosphoinositide phosphatases differentially affect breast cancer progression.

Key messageSelectiveArabidopsis thalianainositol phosphate kinase functions modulate response amplitudes in innate immunity by balancing signalling adjustments with phosphate homeostasis networks.Pyrophosphorylation of InsP6 generates InsP7 and/or InsP8 containing high-energy phosphoanhydride bonds that are harnessed during energy requirements of a cell. As bona fide co-factors for several phytohormone networks, InsP7/InsP8 modulate key developmental processes. With requirements in transducing jasmonic acid (JA) and phosphate-starvation responses (PSR), InsP8 exemplifies a versatile metabolite for crosstalks between different cellular pathways during diverse stress exposures. Here we show that Arabidopsis thaliana INOSITOL PENTAKISPHOSPHATE 2-KINASE 1 (IPK1), INOSITOL 1,3,4-TRISPHOSPHATE 5/6-KINASE 1 (ITPK1), and DIPHOSPHOINOSITOL PENTAKISPHOSPHATE KINASE 2 (VIH2) implicated in InsP8 biosynthesis, suppress salicylic acid (SA)-dependent immunity. In ipk1, itpk1 or vih2 mutants, constitutive activation of defenses lead to enhanced resistance against the Pseudomonas syringae pv tomato DC3000 (PstDC3000) strain. Our data reveal that upregulated SA-signaling sectors potentiate increased expression of several phosphate-starvation inducible (PSI)-genes, previously known in these mutants. In reciprocation, upregulated PSI-genes moderate expression amplitudes of defense-associated markers. We demonstrate that SA is induced in phosphate-deprived plants, however its defense-promoting functions are likely diverted to PSR-supportive roles. Overall, our investigations reveal selective InsPs as crosstalk mediators in defense-phosphate homeostasis and in reprogramming stress-appropriate response intensities.

Vesicular traffic and membrane contact sites between organelles enable the exchange of proteins, lipids, and metabolites. Recruitment of tethers to contact sites between the endoplasmic reticulum (ER) and the plasma membrane is often triggered by calcium. Here we reveal a function for calcium in the repression of cholesterol export at membrane contact sites between the ER and the Golgi complex. We show that calcium efflux from ER stores induced by inositol-triphosphate [IP 3 ] accumulation upon loss of the inositol 5-phosphatase INPP5A or receptor signaling triggers depletion of cholesterol and associated Gb3 from the cell surface, resulting in a blockade of clathrin-independent endocytosis (CIE) of Shiga toxin. This phenotype is caused by the calcium-induced dissociation of oxysterol binding protein (OSBP) from the Golgi complex and from VAP-containing membrane contact sites. Our findings reveal a crucial function for INPP5A-mediated IP 3 hydrolysis in the control of lipid exchange at membrane contact sites. The interplay between non-vesicular lipid transport, calcium signaling, and membrane dynamics is unclear. Here, the authors report a function for inositol triphosphate hydrolysis by the inositol 5-phosphatase INPP5A in controlling lipid exchange at interorganelle membrane contact sites between the endoplasmic reticulum and Golgi.

Spinocerebellar ataxias 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP). The selective neurodegeneration in the cerebellum in SCA17 raises the question of why ubiquitously expressed polyQ proteins can cause neurodegeneration in distinct brain regions in different polyQ diseases. By expressing mutant TBP in different brain regions in adult wild-type mice via stereotaxic injection of adeno-associated virus, we found that adult cerebellar neurons are particularly vulnerable to mutant TBP. In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated gene transcription to down-regulate INPP5A, a protein that is highly abundant in the cerebellum. CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of wild-type mice leads to Purkinje cell degeneration, and Inpp5a overexpression decreases inositol 1,4,5-trisphosphate (IP 3 ) levels and ameliorates Purkinje cell degeneration in SCA17 knock-in mice. Our findings demonstrate the important contribution of a tissue-specific protein to the polyQ protein-mediated selective neuropathology. It is not yet clear how ubiquitously-expressed proteins can cause the selective degeneration of particular populations of neurons, such as in spinocerebellar ataxia type 17, SCA17, which results from a CAG trinucleotide repeat expansion in the ubiquitously expressed transcription factor TBP. Here, the authors show that mutant TBP suppresses the cerebellum-enriched transcription of Inpp5a and link altered levels of INPP5A to the selective degeneration of cerebellar neurons.

Age‐related macular degeneration (AMD), a leading cause of vision loss affecting retinal pigment epithelial (RPE) cells, remains largely unexplained by current genome‐wide association studies (GWAS) risk variants. Our research on Cryba1, encoding βA3/A1‐crystallin protein, reveals its crucial role in RPE cell function via a novel epigenetic mechanism, also evident in human atrophic AMD samples. Loss of Cryba1 in mouse RPE cells triggers epigenetic changes by reducing histone deacetylase 3 (HDAC3) activity through two mechanisms. First, Cryba1 depletion reduces inositol polyphosphate multikinase (IPMK) expression, which potentially reduces inositol hexakisphosphate (InsP6) generation since IPMK's kinase activity is essential for producing InsP4 and InsP5 as precursors to InsP6. Since InsP4, InsP5, or InsP6 is crucial for HDAC3's interaction with the corepressor's DAD domains, reduced IPMK expression in Cryba1‐depleted cells likely diminishes the HDAC3‐DAD interaction, leading to a reduction in HDAC3's activity. Second, reduced βA3/A1 protein in Cryba1‐deficient cells impairs HDAC3's interaction with casein kinase 2 (CK2), resulting in decreased HDAC3 phosphorylation. Collectively, this increases H3K27 acetylation at the RET promoter region, likely enhancing the transcription of RET, a receptor tyrosine kinase critical for cell survival. Although RET is transcriptionally increased, Cryba1 loss disrupts its protein maturation, causing immature RET protein accumulation. This triggers age‐dependent endoplasmic reticulum (ER) stress, potentially contributing to the pathogenesis of AMD. Interestingly, although Cryba1 is not identified as an AMD‐linked variant in current GWAS, its loss may be linked to AMD mechanisms. These findings underscore the potential of gene‐agnostic and epigenetic therapeutic strategies for treating AMD. βA3/A1‐crystallin regulates HDAC3 activity and epigenetic processes in the RPE. (A) The illustration demonstrates that βA3/A1‐crystallin plays a crucial role in maintaining IPMK protein expression, which in turn activates HDAC3. (B) When βA3/A1‐crystallin is absent (Cryba1 KO ), IPMK protein expression decreases, resulting in the deactivation of HDAC3. This deactivation leads to increased H3K27 acetylation at the RET promoter, subsequently enhancing RET gene transcription. In knockout cells (Cryba1KO) lacking βA3/A1‐crystallin, RET protein maturation is impaired, causing immature RET to accumulate within the cell. This intracellular sequestration of immature RET ultimately triggers endoplasmic reticulum stress.

The src homology 2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 are two proteins involved in intracellular signaling pathways and have been linked to the pathogenesis of several diseases. Both protein paralogs are well known for their involvement in the formation of various kinds of cancer. SHIP1, which is expressed predominantly in hematopoietic cells, has been implicated as a tumor suppressor in leukemogenesis especially in myeloid leukemia, whereas SHIP2, which is expressed ubiquitously, has been implicated as an oncogene in a wider variety of cancer types and is suggested to be involved in the process of metastasis of carcinoma cells. However, there are numerous other diseases, such as inflammatory diseases as well as allergic responses, Alzheimer’s disease, and stroke, in which SHIP1 can play a role. Moreover, SHIP2 overexpression was shown to correlate with opsismodysplasia and Alzheimer’s disease, as well as metabolic diseases. The SHIP1-inhibitor 3-α-aminocholestane (3AC), and SHIP1-activators, such as AQX-435 and AQX-1125, and SHIP2-inhibitors, such as K161 and AS1949490, have been developed and partly tested in clinical trials, which indicates the importance of the SHIP-paralogs as possible targets in the therapy of those diseases. The aim of this article is to provide an overview of the current knowledge about the involvement of SHIP proteins in the pathogenesis of cancer and other human diseases and to create awareness that SHIP1 and SHIP2 are more than just tumor suppressors and oncogenes.

Inositol tris/tetrakis phosphate kinases (IP3-4K) in the human fungal priority pathogens, Cryptococcus neoformans (CnArg1) and Candida albicans (CaIpk2), convey numerous virulence functions, yet it is not known whether the IP3-4K catalytic activity or a scaffolding role is responsible. We therefore generated a C. neoformans strain with a non-functional kinase, referred to as the dead-kinase (dk) CnArg1 strain (dkArg1). We verified that, although dkARG1 cDNA cloned from this strain produced a protein with the expected molecular weight, dkArg1 was catalytically inactive with no IP3-4K activity. Using recombinant CnArg1 and CaIpk2, we confirmed that, unlike the IP3-4K homologs in humans and Saccharomyces cerevisiae, CnArg1 and CaIpk2 do not phosphorylate the lipid-based substrate, phosphatidylinositol 4,5-bisphosphate, and therefore do not function as class I PI3Ks. Inositol polyphosphate profiling using capillary electrophoresis-electrospray ionization-mass spectrometry revealed that IP3 conversion is blocked in the dkArg1 and ARG1 deletion (Cnarg1Δ) strains and that 1-IP7 and a recently discovered isomer (4/6-IP7) are made by wild-type C. neoformans. Importantly, the dkArg1 and Cnarg1Δ strains had similar virulence defects, including suppressed growth at 37°C, melanization, capsule production, and phosphate starvation response, and were avirulent in an insect model, confirming that virulence is dependent on IP3-4K catalytic activity. Our data also implicate the dkArg1 scaffold in transcriptional regulation of arginine metabolism but via a different mechanism to S. cerevisiae since CnArg1 is dispensable for growth on different nitrogen sources. IP3-4K catalytic activity therefore plays a dominant role in fungal virulence, and IPK pathway function has diverged in fungal pathogens.IMPORTANCEThe World Health Organization has emphasized the urgent need for global action in tackling the high morbidity and mortality rates stemming from invasive fungal infections, which are exacerbated by the limited variety and compromised effectiveness of available drug classes. Fungal IP3-4K is a promising target for new therapy, as it is critical for promoting virulence of the human fungal priority pathogens, Cryptococcus neoformans and Candida albicans, and impacts numerous functions, including cell wall integrity. This contrasts to current therapies, which only target a single function. IP3-4K enzymes exert their effect through their inositol polyphosphate products or via the protein scaffold. Here, we confirm that the IP3-4K catalytic activity of CnArg1 promotes all virulence traits in C. neoformans that are attenuated by ARG1 deletion, reinforcing our ongoing efforts to find inositol polyphosphate effector proteins and to create inhibitors targeting the IP3-4K catalytic site, as a new antifungal drug class.

Background Early leaf senescence influences yield and yield quality by affecting plant growth and development. A series of leaf senescence-associated molecular mechanisms have been reported in rice. However, the complex genetic regulatory networks that control leaf senescence need to be elucidated. Results In this study, an early senescence 2 ( es2 ) mutant was obtained from ethyl methanesulfonate mutagenesis (EMS)-induced mutational library for the Japonica rice cultivar Wuyugeng 7 (WYG7). Leaves of es2 showed early senescence at the seedling stage and became severe at the tillering stage. The contents of reactive oxygen species (ROS) significantly increased, while chlorophyll content, photosynthetic rate, catalase (CAT) activity significantly decreased in the es2 mutant. Moreover, genes which related to senescence, ROS and chlorophyll degradation were up-regulated, while those associated with photosynthesis and chlorophyll synthesis were down-regulated in es2 mutant compared to WYG7. The ES2 gene, which encodes an inositol polyphosphate kinase (OsIPK2), was fine mapped to a 116.73-kb region on chromosome 2. DNA sequencing of ES2 in the mutant revealed a missense mutation, ES2 was localized to nucleus and plasma membrane of cells, and expressed in various tissues of rice. Complementation test and overexpression experiment confirmed that ES2 completely restored the normal phenotype, with chlorophyll contents and photosynthetic rate increased comparable with the wild type. These results reveal the new role of OsIPK2 in regulating leaf senescence in rice and therefore will provide additional genetic evidence on the molecular mechanisms controlling early leaf senescence. Conclusions The ES2 gene, encoding an inositol polyphosphate kinase localized in the nucleus and plasma membrane of cells, is essential for leaf senescence in rice. Further study of ES2 will facilitate the dissection of the genetic mechanisms underlying early leaf senescence and plant growth.

Inositol polyphosphate 5-phosphatase (5PTase), a key enzyme that hydrolyzes the 5′ position of the inositol ring, has essential functions in growth, development, and stress responses in plants, yeasts, and animals. However, the evolutionary history and patterns of 5PTases have not been examined systematically. Here, we report a comprehensive molecular evolutionary analysis of the 5PTase gene family and define four groups. These four groups are different from former classifications, which were based on in vitro substrate specificity. Most orthologous groups appear to be conserved as single or low-copy genes in all lineages in Groups II–IV, whereas 5PTase genes in Group I underwent several duplication events in angiosperm, resulting in multiple gene copies. Whole-genome duplication (WGD) was the main mechanism for 5PTase duplications in angiosperm. Plant 5PTases have more members than that of animals, and most plant 5PTase genes appear to have evolved under strong purifying selection. The paralogs have diverged in substrate specificity and expression pattern, showing evidence of selection pressure. Meanwhile, the increase in 5PTases and divergences in sequence, expression, and substrate might have contributed to the divergent functions of 5PTase genes, allowing the angiosperms to successfully adapt to a great number of ecological niches.