Abstract: Polyphosphoinositides (PPIns) are signalling messengers representing less than five per cent of the total phospholipid concentration within the cell. Despite their low concentration, these lipids are critical regulators of various cellular processes, including cell cycle, differentiation, gene transcription, apoptosis and motility. PPIns are generated by the phosphorylation of the inositol head group of phosphatidylinositol (PtdIns). Different pools of PPIns are found at distinct subcellular compartments, which are regulated by an array of kinases, phosphatases and phospholipases. Six of the seven PPIns species have been found in the nucleus, including the nuclear envelope, the nucleoplasm and the nucleolus. The identification and characterisation of PPIns interactor and effector proteins in the nucleus have led to increasing interest in the role of PPIns in nuclear signalling. However, the regulation and functions of PPIns in the nucleus are complex and are still being elucidated. This review summarises our current understanding of the localisation, biogenesis and physiological functions of the different PPIns species in the nucleus.
Protein Domain | Phosphoinositide(s) Bound | References |
---|---|---|
Pleckstrin homology (PH) domain | PtdIns3P, PtdIns4P, PtdIns(4,5)P2, PtdIns(3,4)P2 PtdIns(3,4,5)P3 |
[10,11,12,13,14,33,34,35,36] |
Phox homology (PX) domain | PtdIns3P, PtdIns(3,4)P2, PtdIns(4,5)P2 | [37,38,39] |
Plant homeodomain (PHD) | PtdIns3P, PtdIns5P | [40,41] |
FYVE domain | PtdIns3P | [42] |
ENTH domain | PtdIns(4,5)P2 | [43] |
ANTH domain | PtdIns(4,5)P2 | [44] |
Polybasic domains | PtdIns(4,5)P2 | [45,46,47] |
Tubby | PtdIns(4,5)P2 | [48,49] |
In the early 1980s, key discoveries in nuclear PPIns centred around biochemical studies aimed at ensuring that the nuclear pool of PPIns was not a consequence of contamination from the much larger pool in the cytoplasm (plasma membrane, ER, Golgi) and, subsequently, on demonstrating that the nuclear pool could be regulated distinctly from other pools of PPIns. Further studies began to define nuclear targets that potentially interact with nuclear pools of PPIns, which effectively define downstream signalling pathways. In fact, we now have a plethora of signalling proteins that are nuclear, bind PPIns and potentially impact on all aspects of nuclear functions, though we lack considerable knowledge of how these pathways are controlled and coordinated. We still do not understand how the nuclear pool of PPIns is established, how it is maintained and how it is controlled and manipulated. The first two are rather perplexing, given that the immuno-localisation studies for PtdIns(4,5)P2 suggest that it is highly localised in membrane-less nuclear bodies, such as splicing speckles, islets and the nucleolus. This begs some simple questions. How do PPIns enter the nucleus and, once there, how are membrane-loving lipids maintained in membrane-less compartments or at specific genomic regions? PITP and or SF-1 may provide novel mechanisms to transport PPIns to specific genomic regions, such as promoters, where the exposed inositol head group can be presented to regulate epigenetic signalling. Alternatively, the regulation of subsets of genes by PPIns may occur through selective localisation of genes next to PPIns-rich regions of the nucleus. Proximity-based TSA assays have illustrated how genes that are upregulated often become more closely associated with nuclear splicing speckles where PtdIns(4,5)P2 is localized [208]. Finally, how enzymes that modulate nuclear PPIns are controlled is not well understood, which is critical, as this underpins how environmental cues (growth factors, DNA damage, etc.) impact on the levels of nuclear PPIns pools. In part, this lack of knowledge is driven by the lack of nuclear-specific isoforms that only regulate nuclear pools of PPIns. In most instances, the enzymes shuttle between the two compartments and control their cognate lipid in both compartments. For example, PIP4K2 has a nuclear localisation sequence that allows it to shuttle between compartments [106] and is phosphorylated in response to activation of the p38-MAPK stress pathway [173]. PIP5K1 also shuttles between the cytoplasm and nucleus. PIP5K1 is sumoylated at three different lysine residues, and while sumoylation at lysine 244 controls nuclear entry, sumoylation at lysine 490 controls subnuclear localisation to the nucleolus. Sumoylation at Lys-490 induces association of PIP5K1 with the chromatin silencing machinery, including heterochromatin protein 1 (HP1 ) and the epigenetic histone modification H3K9me3, to inhibit the expression of target ribosomal DNA (rDNA). Phospholipase C 1, which hydrolyses nuclear PtdIns(4,5)P2 to generate DAG and nuclear Ins(1,4,5)P3 shuttles between the cytoplasm and the nucleus. Of the two known isoforms of PLC 1 (1A and 1B), PLC 1B was suggested to be more localised to the nucleus compared to PLC 1A, due to the presence of a nuclear export sequence in an alternatively spliced exon in PLC 1A. PLC 1 is phosphorylated by the P42-MAPK, which leads to an increase in its nuclear activity [209] and subsequent phosphorylation by PKC acts to switch off PLC 1 [210]. Analysing the activity of these enzymes in vivo is even more challenging, given the lack of tools to study phosphoinositide dynamics in real-time in the nucleus. Clearly, we need a much more detailed map of how nuclear PPIns are modulated distinctly to the cytoplasmic pool if specific targeting of the nuclear PPIn pathway is to be used for therapeutic benefit.
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