The oily nucleus- role of phospholipids in genome biology: membrane-directed roles and signaling in the nucleoplasm

Abstract

Phospholipids, widely known for their structural role in cellular membranes, are now also recognized to play pivotal roles in signal transduction, metabolism, and cellular homeostasis. However, the nucleus is often overlooked in the context of phospholipid biology. The dynamic abundance and precise management of the turnover of nuclear phospholipids by dedicated kinases, phosphatases, and phospholipases implies specialized functions. Like the cytoplasm, many of these biological roles occur or are initiated within the nuclear membrane. However, several aspects of nuclear phospholipid biology appear to be based in the nucleoplasm and are mediated by dynamic and soluble lipoprotein complexes. In many cases, the exact working spaces and molecular mechanisms of action of nuclear phospholipids are not yet clearly defined, and their physiology is likely underestimated due to technical challenges. Nonetheless, in recent years, the impact of nuclear phospholipids on the structure and function of the genome has been found to be more multifaceted and complex. In this review, we summarize recent insights into the interactions and biological roles of phospholipids with respect to chromatin, gene regulation, and nuclear physiology, and discuss these roles in the context of two broad functional domains - the nuclear membrane and the nucleoplasm. We argue that a more detailed understanding of the molecular working modes of nuclear phospholipids is crucial to enable their full scientific comprehension, especially when the exploration of the biology of nuclear phospholipids and their dysregulation may offer promising avenues for diagnosis and therapeutic interventions for various genome-linked diseases.

Keywords: Chromatin remodeling; Gene expression; Nuclear membrane; Nuclear signaling; Nucleus; Phosphoinositides; Phospholipids.

Fig. 1

Phospholipids are classified into two major groups based on the presence of different backbones, and further subclassified based on the different head groups (R). (a) General classification of phospholipids. (b) Classification of glycerophospholipids. (c) Classification of sphingophospholipids

Fig. 2

Composition of the eukaryotic cell nucleus. (a) Total lipid, protein, and DNA contents of eukaryotic nuclei and (b) composition of the total nuclear lipid pool

Fig. 3

Phosphatidyl inositol (PtdIns) and its derivatives inside the nucleus. PIP kinases and phosphatases control the phosphorylation states of the hydroxyl groups present on positions 3, 4, and 5 of the inositol head group giving rise to mono, di and tri-phosphorylated phosphoinositides. For abbreviations see text

Fig. 4

Regulation of mRNA export by nuclear PI3K signaling. Export of mRNAs requires a series of events: pre-mRNA processing, ribonucleoprotein targeting to nuclear pore complexes, and translocation through nuclear pores to the cytoplasm. Aly/REF is a physiological target of PI3K signaling that regulates the protein’s localization and function through nuclear Akt-mediated phosphorylation and its association with the phosphoinositide PI(3,4,5)P3

Fig. 5

Various phospholipid-chromatin and -chromatin binding protein interactions are crucial to stabilize nuclear architecture and function. (a) The ING2(PHD)-Sin3a-HDAC1 complex binds PtdIns(5)P, which facilitates its association with chromatin remodeling complexes. (b) PtdIns(5)P influences H3K4me3 and drives gene expression via its interaction with TAF3(PHD). (c) Binding of PtdIns(5)P to UHRF1 regulates its binding to the H3K9me3 chromatin mark. (d) S1P inhibits histone deacetylase HDAC1 and HDAC2. For abbreviations see text

Fig. 6

Phosphoinositide-p53 signalosome: p53-PI3K phosphorylates PtdIns(4,5)P2 to PtdIns(3,4,5)P3, which forms a complex with p53 that initiates a cascade involving activation of Akt and phosphorylation of FOXO to inhibit DNA damage-induced apoptosis

Fig. 7

The complexities of nuclear phospholipid biology. (a) Membrane-bound and/or -directed functions include effects driven by the hydrophobic tails. Phospholipid asymmetry in the outer vs. inner nuclear membrane affects (i) incorporation of specific factors and (ii) controls membrane curvature and fluidity that is sensed by specific proteins. The polar head groups of phospholipids are recognized by (iii) proteins likely anchored in the nuclear membrane or initiate downstream signaling via (iv) direct recruitment of factors or (v) by their metabolites (here membrane-associated or soluble effects are often unclear and difficult to resolve). (b) Some effects of nuclear phospholipids are still quite unclear. These include (i) impacts on chromatin structure/composition, (ii) effects on transcription and (iii) depletion of linker histones from chromatin. (c) Within the nucleoplasm, the hydrophobic tails of phospholipids need to be shielded from the aqueous milieu. It is conceivable that this occurs in (i) micelles (aka homogenous lipid composition), (ii) nuclear lipid droplets (aka heterogenous lipid composition), (iii) nuclear speckles or (iv) other aggregated/phase separated entities. In such scenario, the polar head groups would be available to initiate and control specific signaling events via recruitment of distinct proteins. (v) Alternatively, phospholipids can be fully accommodated by nuclear proteins simultaneously binding their hydrophobic and polar parts. (vi) In the case of PHD finger mediated events, it is yet unclear how the hydrophobic parts of nuclear phospholipids are dealt with biochemically. (vii) Specific signaling events can also be mediated by the exposed polar head groups of nuclear phospholipids when their acyl parts are bound in hydrophobic protein pockets. The question marks indicate aspects of nuclear phospholipid biology that are not fully resolved or hypothetical (order of events, localization of components, biochemistry of interactions, etc.)