Cell Biochemistry And Functions

[Maral Mende]

Acell is a mass of cytoplasm that is bound externally by a cell membrane. Usually microscopic in size, cells are the smallest structural units of living matter and compose all living things. Most cells have one or more nuclei and other organelles that carry out a variety of tasks. Some single cells are complete organisms, such as a bacterium or yeast. Others are specialized building blocks of multicellular organisms, such as plants and animals.

The cell membrane surrounds every living cell and delimits the cell from the surrounding environment. It serves as a barrier to keep the contents of the cell in and unwanted substances out. It also functions as a gate to both actively and passively move essential nutrients into the cell and waste products out of it. Certain proteins in the cell membrane are involved with cell-to-cell communication and help the cell to respond to changes in its environment.

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Being true for all living organisms, accurate spatio-temporal regulation of gene expression is a fundamental mechanism underlying development, homeostasis and adaptation to the environment. Eukaryotic gene expression is a cumulative outcome of a multitude of molecular processes, including transcription, mRNA splicing, stability and translation, chromatin modification, as well as protein stability and modification. Each of these processes is in turn controlled by a highly dedicated repertoire of proteins. However, one protein, Tudor staphylococcal nuclease (TSN, also known as Tudor-SN, SND1 or p100) appears to act in most of the gene expression pathways.

TSN is an evolutionarily conserved protein found in all eukaryotic lineages, except budding yeast, Saccharomyces cerevisiae. Conservation along significant evolutionary distance suggests important physiological functions for TSN. Invariant domain composition of TSN comprises tandem repeat of four staphylococcal nuclease (SN)-like domains (hereafter referred to as SN domains) at the N terminus and a fusion of a Tudor domain with a partial SN domain at the C terminus (Figures 1a and b).1, 2, 3 The simultaneous presence of both Tudor and SN domains in the same protein molecule is intriguing and suggests that during evolution TSN might have acquired novel molecular functions in addition to canonical Tudor- and SN-specific functions. Indeed, owing to the presence of multiple domains TSN protein can interact with nucleic acids, individual proteins and protein complexes in a promiscuous manner.4

Domain composition and tertiary structure of TSN. (a) TSN has invariant domain architecture including a tandem of four SN-like domains followed by a Tudor domain and a fifth SN domain. (b) The ribbon model of truncated human TSN.17 Tudor domain and three SN domains are colored in brown and blue, respectively

TSN was initially discovered as a transcriptional co-activator interacting with Epstein-Barr nuclear antigen 2 (EBNA2) and promoting EBNA2-dependent transcription.1, 5 Importantly, TSN can also act as a co-activator of several other transcription factors, such as Signal transducer and activator of transcription 5 (STAT5) (ref. 6) and STAT6 (ref. 7). Besides transcriptional role, TSN has been subsequently shown to function in post-transcriptional regulation, including RNA interference (RNAi), splicing and both degradation and stabilization of mRNA. Participation of TSN in several gene regulatory pathways appears to correlate with its ability to shuttle between nucleus and cytoplasm8, 9 and under certain conditions to re-localize to cytoplasmic foci.10, 11, 12

To-date TSN is known to be critically involved in virtually all pathways of gene expression, ranging from transcription to RNA silencing. Moreover, increased expression of TSN has been found to be closely associated with various types of cancer.13, 14, 15 Considering ever increasing interest to further understand a multitude of TSN-mediated processes and a mechanistic role of TSN in these processes, here we took an attempt to summarize and update the available information about this intriguing multifunctional protein.

A combination of the modeled three-dimensional structures and X-ray crystallography revealed that four N-terminally localized SN domains resemble a stick and the C-terminal Tudor fused to a partial SN domain resemble a hook (Figure 1b).16, 17 This indicates that different parts of TSN protein may recruit diverse protein complexes to perform various functions (Figure 2).

Multi-domain composition of TSN enables interaction with functionally diverse repertoires of proteins. TSN is involved in numerous cellular pathways via interactions with key components of these pathways, through distinct domains. Thus, N-terminal SN domains act as a bridge between several components of the basal transcription machinery such as EBNA2-TFIIE, STAT6-RHA, C-Myb-Pim1, STAT6-PC1 and STAT6-CBP. In addition, TSN interacts through SN domains with the transcription factor PPARγ, several components of the RISC complex, including AEG-1, Ago1 and Ago2, and with different SG-associated proteins, such as ADAR1, G3BP, TIAR, Pabp1 and eIF4E. C-terminal Tudor domain interacts with several components involved in RNA splicing, including the Sm proteins SmB, SmD1/D3, SmD1, SAM68 and Prp8. In addition, C-terminal Tudor domain interacts with the Piwi protein PIWIL1/Miwi

The SN domains belong to the oligonucleotide/oligosaccharide-binding fold (OB-fold) superfamily remarkably conserved throughout evolution and comprising proteins that participate in nucleic acid binding.1, 18 Each SN domain consists of the characteristic five-stranded β-barrel (OB-fold) flanked by three α-helices (Figure 1b). In fact, the presence of SN domains indicates that TSN could share the primary function of bacterial enzyme, that is, nucleic acid binding and processing.1, 9, 10, 19, 20 The C-terminally situated SN domains of TSN specifically interact with several components of RNA-induced silencing complex (RISC) such as the protein astrocyte elevated gene-1 (AEG-1), Argonaute 1 (Ago1) and 2 (Ago2) (Figure 2). In addition, human TSN is directly involved in the degradation of hyper-edited double-stranded RNA (dsRNA) and miRNA precursors produced by adenosine deaminases acting on RNA (ADARs) enzymes.21 Notably, human TSN interacts with ADAR1, RNA-binding Ras-GAP SH3 binding protein (G3BP) and with several core components of stress granules (SGs) under stress conditions, whereupon SN domains are essential for both interaction and SG-specific localization of TSN (Figure 2 and Table 1).3, 11, 22 Apart from binding cytoplasmic partners, SN domains of mammalian TSN bind several components of basal transcription machinery in the nucleus (Figure 2). All these findings suggest that TSN, through its SN domains, may participate in both transcriptional and post-transcriptional regulation of gene expression.

Because of the cross-kingdom conservation of TSN sequence and its molecular structure, this protein might perform similar functions in different organisms. Indeed, both animal and plant TSN proteins interact with several SG-associated proteins11, 12, 35, 36 and control the fate (stabilization or degradation) of specific mRNAs during stress.10, 36, 37, 38 However, lineage-specific intracellular localization of TSN raises doubts about cross-kingdom conservation of all TSN functions. For example, unlike nuclear-cytoplasmic localization of TSN in animal cells, plant TSN is exclusively cytoplasmic, indicating that the probability of its involvement in transcriptional regulation and splicing in plants is low.10, 38

TSN has been postulated to act as a transcriptional co-activator, interacting with several transcription factors (Figure 2 and Table 1). Thus, TSN functions as a bridge coupling promoter-specific transcription factors and the basal transcription machinery, such as c-Myb and Pim-1 (ref. 39), STAT6 and CREB-binding protein (CBP),40 STAT6 and RNA Helicase A (RHA),41 STAT6 and polycystin-1 (PC1),42 EBNA2 and TFIIE,5 respectively (Figure 2). In addition, TSN interacts with STAT5 (ref. 6), peroxisome proliferator-activated receptor-γ (PPARγ)43 and the nuclear factor kB (NF-kB) (Table 1).44 The interaction with transcription factors is mediated by SN domains, which concurrently bind DNA.6, 7 Accordingly, a set of TSN-bound promoter regions has been recently identified using chromatin immunoprecipitation.26 The interaction of TSN with multiple components of transcription machinery makes it an important factor in the regulation of a plethora of cellular signaling pathways implicated in the pathogenesis of various human diseases.

TSN is critical for assembly of STAT transcriptosome, participating in cell proliferation, cell death, and differentiation.45 Thus, TSN interaction with STAT6 and PC1 activates renal epithelial cell proliferation in autosomal dominant polycystic kidney disease (ADPKD).42 Binding of TSN and STAT6 to CBP stimulates the expression of interleukin-4, an important regulator of immune and anti-inflammatory response. Interaction of TSN with STAT5 facilitates the transcriptional activation of prolactin (PRL) genes.6 STAT proteins undergo phosphorylation and subsequent dimerization upon cytokine stimulation, facilitating their nuclear import and activation of transcription of target genes.46 Given that TSN has been detected in both the cytoplasm and nucleus, the interaction of TSN with STAT proteins might occur already in the cytoplasm, and the pre-formed complex could be translocated to the nucleus. Although the function of TSN as transcriptional co-activator has been only described in human cells, a yeast two-hybrid analysis performed in the malaria parasite P. falciparum suggested, albeit not proved exclusively, a similar role for TSN in protozoa.33

3a8082e126