Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor in Multiple Myeloma

Inositol polyphosphate-4-phosphatase type II (INPP4B) has been identified as a tumor suppressor, while little is known about its expression and function in multiple myeloma (MM). In this study, we evaluated the expression of INPP4B in 28 cases of newly diagnosed MM patients and 42 cases of extramedullary plasmacytoma (EMP) patients compared with normal plasma cells and found that low INPP4B expression was correlated with poor outcomes in MM patients. Moreover, expression of INPP4B in seven MM cell lines was all lower than that in normal plasma cells. In addition, loss of function of INPP4B promoted cell proliferation in MM cells; however, gain of function suppressed MM cells proliferation and arrested the cell cycle at G0/G1 phage. Meanwhile, knockdown of INPP4B enhanced resistance, but overexpression promoted sensitivity to bortezomib treatment in MM cells. Mechanistically, we found that INPP4B exerted its role via inhibiting the phosphorylation of Akt at lysine 473 but not threonine 308, which attenuated the activation of the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Therefore, we identified an inhibitory effect of INPP4B in MM, and our findings suggested that loss of INPP4B expression is a risk factor of aggressive MM.

Intestinal epithelial IPMK protects mice from experimental colitis via governing colonic tuft cell development

As a pleiotropic signaling factor, inositol polyphosphate multikinase (IPMK) is involved in key biological events such as growth and innate immunity, acting either enzymatically to mediate the biosynthesis of inositol polyphosphates and phosphatidylinositol 3,4,5-trisphosphates, or noncatalytically to control key signaling target molecules. However, the functional significance of IPMK in regulating gut epithelial homeostasis remains largely unknown. Here we show that intestinal epithelial-specific deletion of IPMK aggravates dextran sulfate sodium (DSS)-induced colitis with higher clinical colitis scores and elevated epithelial barrier permeability. No apparent defects in PI3K-AKT signaling pathway and pro-inflammatory cytokine production were found in IPMK-deficient colons challenged by DSS treatment. RNA-sequencing and FACS analyses further revealed significantly decreased tuft cells in IPMK-deficient colons. Importantly, IPMK deletion in the gut epithelium was found to decrease choline acetyltransferase (ChAT) but not IL-25, suggesting selective loss of cholinergic signaling. Thus, these findings identify IPMK as a physiological determinant of tuft cell differentiation and highlight the critical function of IPMK in the control of gut homeostasis.

IPMK physically binds to the SWI/SNF complex and modulates BRG1 occupancy

ABSTRACTInositol polyphosphate multikinase (IPMK), a key enzyme in the inositol polyphosphate (IP) metabolism, is a pleiotropic signaling factor involved in major biological events including transcriptional control. In yeasts, IPMK and its IP products were known to promote the activity of SWI/SNF chromatin remodeling complex, which plays a critical role in gene expression by regulating chromatin accessibility. However, the direct linkage between IPMK and chromatin remodelers remains unclear, raising a question on how IPMK contributes to the transcriptional regulation in mammals. By employing unbiased screenings and in vivo/in vitro immunoprecipitations, here we demonstrated that IPMK physically associates with native mammalian SWI/SNF complexes by directly binding to SMARCB1, BRG1, and SMARCC1. Furthermore, we identified the specific domains required for the IPMK-SMARCB1 binding. Notably, using CUT&RUN and ATAC-seq assays, we discovered that IPMK co-localizes with BRG1 and regulates BRG1 localization as well as BRG1-mediated chromatin accessibility in a genome-wide manner (including promoter-TSS) in mouse embryonic stem cells. Finally, our mRNA-seq analyses revealed that IPMK and SMARCB1 regulate common gene sets, validating a functional link between IPMK and SWI/SNF complex. Together, these findings establish an importance of IPMK in promoter targeting of the SWI/SNF complex, thereby contributing to SWI/SNF-meditated chromatin accessibility and transcription.

Novel pathogenic OCRL mutations and genotype–phenotype analysis of Chinese children affected by oculocerebrorenal syndrome: two cases and a literature review

Background Oculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by congenital cataracts, mental retardation, and proximal tubulopathy. This condition is caused by a mutation of OCRL gene (located at chromosome Xq26.1), which encodes an inositol polyphosphate 5-phosphatase. Case presentation We identified two novel OCRL mutations in two unrelated Chinese boys, each with a severe phenotype of Lowe syndrome. A novel de novo deletion (hemizygous c.659_662delAGGG, p.E220Vfs*29) was present in patient 1 and a novel splicing mutation (hemizygous c.2257-2A > T) that was maternally inherited was present in patient 2. A renal biopsy in patient 2 indicated mild mesangial proliferative glomerulonephritis, mild focal mononuclear cells infiltration, and interstitial focal fibrosis. Moreover, renal expression of OCRL-1 protein in patient 2 was significantly reduced compared to a control patient with thin basement membrane disease. Conclusions This study reports two novel OCRL variants associated with severe ocular and neurologic deficiency, despite only mild renal dysfunction. Based on our two patients and a literature review, the genotype–phenotype correlation of OCRL mutations with this severe phenotype of Lowe syndrome suggest a possible clustering of missense, deletion, and nonsense mutations in the 5-phosphatase domain and Rho-GAP domain in the Chinese population.

Mechanistic insights into the regulation of plant phosphate homeostasis by the rice SPX2 – PHR2 complex

Phosphate (Pi) is a key macronutrient limiting plant growth and crop productivity. In response to the nutrient deficiency, Pi starvation response (PHR) transcription factors activate Pi starvation induced (PSI) genes. PHR transcription factors are negatively regulated by stand-alone SPX proteins, cellular receptors for inositol pyrophosphate (PP-InsP) nutrient messengers. How PP-InsP-bound SPX domains interact with PHR transcription factors is poorly understood. Here, we report crystal structures of the rice SPX2/InsP6/PHR2 complex and of the PHR2 DNA binding (MYB) domain in complex with its target DNA at resolutions of 3.1 Å and 2.7 Å, respectively. Inositol polyphosphate binding causes SPX2 to assemble into a domain-swapped dimer. The signalling-active SPX2 dimer binds two copies of PHR2, targeting both its coiled-coil (CC) oligomerisation domain and its MYB domain. Structural comparisons, biochemical analyses and genetic characterizations reveal that the SPX2 senses InsP6 / PP-InsPs to inactivate PHR2 by establishing severe steric clashes with the PHR2 MYB domain, preventing DNA binding, and by disrupting oligomerisation of the PHR2 CC domain, attenuating promoter binding. The complex structure rationalizes how PP-InsPs activate SPX receptor proteins to target PHR family transcription factors and provides a mechanistic framework to engineer crops with improved phosphate use efficiency.