The GTP-binding family of proteins, septin, are a very diverse and complex group. Although septins were originally found in yeast, they have now been determined to play important roles in eukaryotic cells among animals and fungi. Within humans, septins function in multiple processes including cytokinesis, neurogenesis, oncogenesis and many more. The family septin contains 14 loci, Sept1-Sept14, which codes for various other septin proteins. The overexpression and mutation of these proteins have been shown to be associated with a multitude of conditions and diseases such as different cancers, Alzheimer’s disease and Parkinson’s disease. Within the following review, the structure, function and role of septin proteins in human conditions and diseases are analyzed. Throughout this work, septin genes will be referred to as “Sept” and septin proteins will be referred to as “SEPT”. Septins are a group of biologically conserved cytoskeletal GTPases that are able to self-assemble, bind to cell membranes and utilize polymerization mechanisms (Valadares et al, 2017). Their function relies heavily on their simple, yet diverse, structure (Figure 1). Septins contain a polybasic region, GTP-binding domain and C- and N-terminal domains (Peterson and Petty, 2010). The C- and N-terminal ends can vary in types and order of amino acids, in addition to having varying chain lengths. The N-terminal is the site responsible for cytoskeletal and membrane interactions, while the C-terminal portion influences inter-filament cross-bridges (Valadares et al, 2017). The GTP-binding domain plays a key role in the stability of the septin’s oligomerizing interfaces through its ability to cause conformational changes (Dolat, Hu, and Spiliotis, 2014). The family of human septin genes are categorized into four groups: Sept-2, Sept-3, Sept-6, and Sept-7. The Sept-2 group contains Sept-1, Sept-2, Sept-4 and Sept-5; the Sept-3 group contains Sept-3, Sept-9 and Sept-12; the Sept-6 group contains Sept-6, Sept-8, Sept-10, Sept-11 and Sept-14; and the Sept-7 group is only made up of Sept-7 and Sept-13 (Valadares et al, 2017 and Cao et al, 2009).
Due to the lack of significant evidence within humans, Sept-13 was originally not included in these categories. With this information, it is now thought to be possible for septin 7 to be interchangeable with septin 13 (Cao, Yu, Wu and Yu, 2009). Additional research conducted on the biological analysis of mammalian septin complexes suggest that SEPT genes in specific groups are able to be utilized as substitutes for the original group listings; for example, since Sept-11 is a part of the Sept-6 group, Sept-11 can substitute for Sept-6 in certain complexes (Nagata et al, 2004). Each group is able to form complexes with their interacting partners and provide varying functional roles. Each function contributes to many pathways and cellular functions. Looking into how their overexpression or mutations assist in the development of diseases could provide vital insight into future septin therapies. Septin oligomeric complexes have been determined to have many putative functions. To date, these complexes are known to participate in cytokinesis, filament formation, neurotransmitter release, microtubule stability, vesicle trafficking and targeting, exocytosis, platelet biology, Rho signaling, cell proliferation, oncogenesis, and testicular biology (Peterson and Petty, 2010). In order to contribute to these functions, septins must interact with the appropriate septin family member(s).
For example, researchers have shown that the SEPT2, SEPT6 and SEPT7 complex has a role that contributes to filament formation and a visual of this complex may be seen in Figure 2 (Low and Macara, 2006). Additionally, SEPT4 and SEPT 8 complexes have been determined to participate in platelet biology (Blaser et al., 2004). Septin complexes can also be formed by proteins that are coded by septin genes which then interact with septin family members. A few of the different complexes and their presumed function are summarized in Table 1 (Peterson and Petty, 2010). Studies have also been conducted to determine whether septins have a significant role in embryogenic processes. Model organisms such as Drosophila and C. elegans have been utilized to gain a better understanding of septin’s developmental roles, but further research is still needed in order to determine their role in mammalian embryonic developmental processes (Dolat, Hu, and Spiliotis, 2014). Although all functions of septin protein complexes are not known, the processes they are known to participate in can lead to better understandings within fields dealing with cancers, the immune system, neurological disorders, and so on. Of the 14 septins, only a one has been determined to be a contributing factor to cancer development. The Sept-9 gene, as previously shown in Table 1, is responsible for coding proteins that participate in cell proliferation.
This gene is capable of acting as an oncogene or as a tumor suppressor gene. The septin 9 gene has been determined to participate in several diseases such as leukemia, brain tumor formation, urologic cancer, ovarian cancer, and breast cancer (Toth et al, 2011). More recent investigations have been focusing on the hypermethylation of the septin9 protein and mRNA overexpression targeting. Previous research has shown that Sept-9 plays a vital role in colorectal cancer and has also been identified in human breast cancer cell lines (Montagna et al, 2003 and Wasserkort et al, 2013). Within colorectal cancer studies, methylation patterns of the Sept-9 gene were analyzed in diseased colon mucosa. Due to the Sept-9 gene containing multiple CpG islands, aberrant hypermethylation was determined to occur in one of its CpG islands, leading to the disruption of different transcript expression (Wasserkort et al, 2013). Seeing that Sept-9 codes for cell proliferating proteins, its epigenetic deregulation was shown to play a role in the development of colorectal cancer (Wasserkort et al, 2013). Additional studies conducted on mouse mammary gland adenocarcinomas and human breast cancer cell lines were also shown to have an overexpression of the Sept-9 gene. Findings suggest that increased levels of Sept-9 correlates with the downregulation of two proteins, Thsp1 and Bax, that regulate apoptotic responses through signaling cascades in mammary tumor formation (Montagna et al, 2003). With Sept-9 also being a common target for mRNA overexpression, it was determined that cellular pathways which aid in oncogenic stimulus independent tumorigenesis gain an advantage in the presence of increased levels of Sept-9 (Montagna et al, 2003). Overall, evidence shows that the Sept-9 overexpression aids in the accelerated mitotic characteristics of malignant cells within diverse mouse models of human breast cancer and in human breast cancer cell lines (Montagna et al, 2003).
Disruptions within the septin genes have also been associated with neurodegenerative conditions including, but not limited to, Alzheimer’s disease and Parkinson’s disease. Of the 14 human septin genes, only 4 have been discovered to have an effect on neurological diseases. Sept-2 (NEDD5), Sept-1 (DIFF6) and Sept-4 (H5) are specifically associated with Alzheimer’s neurofibrillary tangles (Kinoshita et al, 1998). The fourth septin gene is Sept-5 (CDCrel-1) and it is known to be associated with Parkinson’s disease (Peterson and Petty, 2010). Within a study focused on septins in neurofibrillary tangles (NFTs) in Alzheimer’s disease patients, there were 3 septins that were identified to accumulated in NFTs. NFTs are said to be related to the severity of dementia and specific septins have been determined to aid in the formation of pre-tangles, leading to NFTs (Kinoshita et al, 1998). A significant concentration of the human septin proteins Nedd5, H5 and Diff6 were commonly found in or around NFTs within Alzheimer’s Disease patient brains (Kinoshita et al, 1998). They were additionally concentrated in dystrophic neurites in senile plaques and neuropil threads in postmortem Alzheimer’s patients’ brains (Kinoshita et al, 1998).
The overall take away provides great insight to how the overexpression of these genes can contribute to the Alzheimer’s disease. Further studies into this subject will provide more detailed information regarding the molecular mechanisms of NFT formation and ways for combatting it. Compared to Alzheimer’s disease, Parkinson’s disease was originally thought to involve only one septin that plays an almost negligible role. Mutations in the ubiquitin E3 ligase, Parkin, is known as one of the most common causes of Parkinson’s disease (Dawson and Dawson, 2010). Studies have been conducted and determined that Parkin is involved in the degradation of the septin CDCrel-1. CDCrel-1 functions are associated with synaptic vesicles and regulation of secretion (Dawson and Dawson, 2010). Although the first parkin substrate to be identified was CDCrel-1, more recent investigations have determined that SEPT4 is another parkin substrate that is currently under more analyzation (Chesi et al, 2012). SEPT4 is a component of presynaptic scaffolds and Lewy bodies, or abnormal deposits of protein. Lewy bodies are able to promote difficulties in cognition, movement and behavior (Dickson et al, 2008).
The functional loss of Parkin is capable of resulting in a significant collection of the SEPT4 and CDCrel-1 substrates. (Chesi et al, 2012). Further studies in the investigation of these specific septin dysregulations found a significant amount of postmortem human brains with Parkinson’s disease, schizophrenia and bipolar disorders, suggesting that there is an additional positive correlation with septin expression and neurological issues (Ageta-Ishihara et al, 2013). Other notable conditions associated with mutations in septin genes includes the role in causing male infertility. Sept-12 has been distinguished as a testis-specific gene (Kuo et al, 2012). It plays an important role in terminal differentiation of male germ cells and its disruption can lead to two missense mutations, c.266C>T/p.Thr89Met (SEPT12T89M) and c.589G>A/p.Asp197Asn (SEPT12D197N), causing infertility (Kuo et al, 2012). Within the study, The c.266C>T/p.Thr89Met mutation was determined to cause the reduction of guanosine-5’-triphosphate (GTP) hydrolytic activity and patients with SEPT12T89M experienced asthenoteratozoospermia, while the c.589G>A/p.Asp197Asn mutation was determined to cause disruptions in GTP binding and patients with SEPT12D197N experienced oligosthenozoospermia (Kuo et al, 2012). Due to these missense mutations, which caused disturbances in filament formation, the sperm structural integrity was impaired, suggesting that Sept-12, and its coded protein SEPT12, plays a crucial role in the male fertility/infertility (Kuo et al, 2012). Research has shown that 14 human septin genes are capable of contributing to or promoting quite serious diseases. This can be attributed to their ability to have a large assortment of functions when formed into specific protein complexes. From participating in cell division to its role in synaptic vesicle trafficking, the tight regulation of these genes is crucial in maintaining appropriate filament assembly and other common cellular functions. Mutations and other disruptions of these septin genes have been shown to be involved in neurodegenerative condition, such as Alzheimer’s and Parkinson’s disease, different forms of cancer, such as colon and breast cancer, and male infertility. Further investigation of these genes will provide great insight into the different molecular mechanisms behind these conditions, in addition to possible septin therapies that could aid in their preventions.
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