Depletion of mRNA export regulator DBP5/DDX19, GLE1 or IPPK that is a key enzyme for the production of IP6, resulting in differentially altered cytoplasmic mRNA expression and specific cell defect

Abstract

DBP5, also known as DDX19, GLE1 and inositol hexakisphosphate (IP6) function in messenger RNA (mRNA) export at the cytoplasmic surface of the nuclear pore complex in eukaryotic cells. DBP5 is a DEAD-box RNA helicase, and its activity is stimulated by interactions with GLE1 and IP6. In addition, these three factors also have unique role(s). To investigate how these factors influenced the cytoplasmic mRNA expression and cell phenotype change, we performed RNA microarray analysis to detect the effect and function of DBP5, GLE1 and IP6 on the cytoplasmic mRNA expression. The expression of some cytoplasmic mRNA subsets (e.g. cell cycle, DNA replication) was commonly suppressed by the knock-down of DBP5, GLE1 and IPPK (IP6 synthetic enzyme). The GLE1 knock-down selectively reduced the cytoplasmic mRNA expression required for mitotic progression, results in an abnormal spindle phenotype and caused the delay of mitotic process. Meanwhile, G1/S cell cycle arrest was observed in DBP5 and IPPK knock-down cells. Several factors that function in immune response were also down-regulated in DBP5 or IPPK knock-down cells. Thereby, IFNβ-1 mRNA transcription evoked by poly(I:C) treatment was suppressed. These results imply that DBP5, GLE1 and IP6 have a conserved and individual function in the cytoplasmic mRNA expression. Variations in phenotype are due to the difference in each function of DBP5, GLE1 and IPPK in intracellular mRNA metabolism.

Primate lentiviruses require Inositol hexakisphosphate (IP6) or inositol pentakisphosphate (IP5) for the production of viral particles

“…Alternatively, IPPK and IP6 have been shown to play roles in many cellular pathways that may have negative effects on virus production. For example, IP6 is involved in the activation of histone deacetylase-1 and mRNA export, with IPPK knock-down causing G1/ S phase arrest [41,42]. The IPPK-KO cells proliferate more slowly than HEK293FT cells, in concordance with these data.…”

Mechanisms and consequences of subcellularRNAlocalization across diverse cell types

“…Developmental disorders attributed to the disruption of RNA localization patterns are continuing to be discovered. Loss of the RBP Gle1 disrupts centrosomal RNA localization and centrosome function in human cells, leading to lethal motor neuron disease and fetal hydrops 158–160 . Dyskeratosis Congenita is a stem cell disorder caused by the mislocalization of TERT transcripts from Cajal bodies to nucleoli, resulting in telomerase shortening in patient stem cells 161 and predisposing affected individuals to aplastic anemia.…”

The Impact of Post-transcriptional Control: Better Living Through RNA Regulons

“…Interestingly, even these workhorses of the bulk mRNA export pathway have additional functions in stress granule formation and translation ( Aditi et al, 2015 ; Aryanpur et al, 2017 ; Mikhailova et al, 2017 ). Further, beyond common mRNA targets, these export regulators have their own distinct target transcripts, which results in differing cellular phenotypes observed upon their depletion ( Okamura et al, 2018 ). In all, this provides an example of how eIF4E can re-wire the nuclear pore to enhance export of its target transcripts while simultaneously modulating the machinery for bulk mRNA export.…”