European Journal of Cell Biology
Volume 95, Issue 1,
January 2016
, pages 26-41
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Abstract
Gelsolin, a multifunctional actin-binding protein, plays a role that is still not fully understood in tumorigenesis. Therefore, the aim of this study was to identify additional gelsolin molecular partners in human melanoma cells, separately in the cytoplasmic compartment and cell nuclei. To this end, we performed immunoprecipitation experiments based on a modified protocol followed by mass spectrometry. The obtained results were confirmed by Western blot analysis, proximity binding assays and confocal microscopy. As expected, gelsolin interacted with actin, in particular we demonstrated its interaction with cytoplasmic β and γ actins and a newly discovered actin isoform, actbl2. We have identified the ribosomal protein Rpsa, also known as the non-integrin laminin receptor (LamR), and the heterogeneous nuclear ribonucleoprotein hnRNP U as new interaction partners with gelsolin. Our data also indicate that gelsolin interacts with specific components of three cytoskeleton systems: nestin (intermediate filaments), Arp3 ( actin cytoskeleton) and β-tubulin (microtubules). We also report for the first time that gelsolin is a component of intermediate bodies, a tubulin-containing structure formed at the end of cytokinesis.
Entry
Gelsolin is a multifunctional actin binding protein and is involved in the dynamic reorganization of the actin cytoskeleton due to its capping, cleavage and, under certain circumstances, nucleation (Mannherz et al., 2010, Nag et al., 2013). Gelsolin is a member of the actin-binding protein (AbP) family of the gelsolin/villin family and is characterized by six homologous segments of approximately 14 kDa (Kwiatkowski et al., 1986). Gelsolin is found on the tips of lamellipodia or podosomes and invadopodia (Attanasio et al., 2011, Cervero et al., 2012, Mazur et al., 2010), i.e. on the structures responsible for the migration of macrophages and cancer cells. Gelsolin has also been localized in the cell nuclei of various types of cancer cells, including in astrocytoma (Ohnishi et al., 2009), in colorectal cancer cell subpopulations (Zhuo et al., 2012), and in melanoma cell lines (our unpublished observations), but its possible nuclear function is still not fully elucidated. Among members of the gelsolin family, only supervillin has a nuclear localization sequence (NLS), while gelsolin has neither an NLS nor a nuclear export signal (NES) (Li et al., 2012). Published data show that intracellular gelsolin exists in various states of activation, including free gelsolin and Ca2+bound gelsolin, but only free gelsolin can translocate to the nucleus (Van den Abbeele et al., 2010). On the other hand, it has been found that gelsolin can enter the cell nucleus in complex with a steroid hormone and its receptor (Ambrosino et al., 2010, Nishimura et al., 2003). Nishimura et al. (2003) postulated that the formation of the androgen:androgen-receptor:gelsolin complex is crucial for the interaction of the nuclear actin-activated receptor with RNA polymerase II. Although these data suggest that steroid hormones may be responsible for the nuclear localization of gelsolin in melanoma cells, we postulate that gelsolin may have additional functions in the cell nucleus. Indeed, recent data describes the interaction of gelsolin with FBXO25, an F-box protein that serves as a specificity factor for ubiquitin ligases found mainly in the nuclear domains associated with FBXO25 (FAND) (Teixeira et al., 2010).
Recent reports suggest that gelsolin plays a role in tumorigenesis as both a tumor suppressor and tumor promoter. These conflicting hypotheses are based on observations of a decrease in gelsolin levels (GSN)for example breast, bladder, colon, stomach, kidney, lung, oral, ovarian, pancreatic and prostate cancers (as reviewed by Li et al. (2012)) or upregulated in non-small cell lung cancer, urothelial carcinoma, pancreas and (Rao et al., 2002, Shieh et al., 2006, Thompson et al., 2007, Yang et al., 2004). Interestingly, biphasic gelsolin expression was observed during the transition from oral precancerous lesions to oral cancer (Shieh et al., 2006).GSNdownregulation was observed in precancerous lesions, whileGSNupregulation has been observed in oral cancer progression. In addition, gelsolin has been shown to positively stimulate the proliferation, migration and invasion of human oral squamous cell carcinoma cells (Deng et al., 2015).
We have previously shown that gelsolin is critical for the migration and invasion of colon adenocarcinoma and melanoma cell lines (Litwin et al., 2012, Litwin et al., 2009). In colon adenocarcinoma cells, overexpression of gelsolin resulted in an increase, while downregulationGSNexpression in melanoma cells resulted in reduced migration potential. In both cases, we observed dramatic changes in the organization of the actin cytoskeleton, i.e. a reduced polymerization state in gelsolin overexpressing cells and an increase in cytoplasmic stress fibers in gelsolin suppressed cells, reflecting the well-known actin cleavage activity. actin from gelsolin. However, gelsolin was present in A375 cell nuclei even 72h after downregulation was startedGSNexpression, although the amount of gelsolin clearly decreased in the cytoplasmic compartment (Litwin et al., 2012). These intriguing observations inspired us to investigate nuclear gelsolin and its possible interaction partners in more detail. For this study, we selected established cell lines derived from human melanoma and aimed to identify gelsolin's molecular partners, with particular emphasis on possible gelsolin nuclear interaction partners.
To this end, we optimized the procedure for immunoprecipitation of endogenous gelsolin from whole cell lysates (WCL) and nuclear fractions (NF) of melanoma cells. Since our aim was to focus on downstream interactions of endogenous gelsolin, we did not use cells transfected with overexpressed tagged gelsolin. Liquid chromatography/mass spectrometry (LC/MS) analysis of co-immunoprecipitated complexes (Co-IP) led to the identification of novel protein partners interacting with endogenous gelsolin. The specificity of these partners was further confirmed by Western blotting (WB), proximity binding assay (PLA) and colocalization microscopic analyses. We believe that our data may have interesting implications for human melanoma biology and may initiate further research into the role of gelsolin in cancer cells.
section excerpts
Antibodies and dyes
Rabbit anti-emerin (FL-254), mouse anti-GAPDH (H-12), goat anti-gelsolin (C-20), mouse anti-hnRPU U (3G6), rabbit anti-laminin-R (H-141) , goat anti-Laminin-R (F-18), mouse anti-nestin (10c2), rabbit anti-Arp3 (H-110), goat anti-HA (Y-11) and normal goat IgG were obtained from Santa Cruz Biotechnology®Inc. (Heidelberg, Germany). Mouse anti-β-actin (AC-15), mouse anti-γ-actin (2-2.1.14.17), mouse anti-all isoactin (AC40), rabbit anti-all isoactin (C-11), mouse anti-β- tubulin (TUB 2.1) and
Identification of gelsolin in melanoma cell nuclei
We first compared the quality of goat polyclonal and mouse anti-gelsolin monoclonal antibodies by Western blotting (WB) and confocal microscopy, as goat IgG was used for immunoprecipitation and immunostaining experiments, and mouse antibodies were used for Co-IP Western blotting and immunostaining. Evaluation of the results showed that both types of antibodies were specific for gelsolin and recognized a single band of 82 kDa (Supplementary Fig. 1A, B). We also observed
Discussion
To identify novel molecular partners of gelsolin, we co-immunoprecipitated endogenous gelsolin from whole cell lysates (WCL) and nuclear fractions (NF) of melanoma cells using a modified immunoprecipitation protocol. The identification of actin, SERBP1 (SERPINE1 mRNA-binding protein) (Supplementary Table 3) and drabrin (Supplementary Table 5) as gelsolin interaction partners in the LC/MS analysis of coimmunoprecipitates provided a proof of principle for our approach, as there was a seance
Conflict of interest
The authors declare no competing financial interest.
Thanks
AJM, TR and AM thank youFoundation for Polish Sciencefor financial support under the HOMING Plus Program (HOMING Plus/2010-2/8) under the Innovative Economy Program of the European Union. Special thanks go to Ilona Styczeń for her important administrative contribution to this work. The costs of publication were financed from the program of the Wrocław Center for Biotechnology "National Center for Leading Research (KNOW)" for the years 2014-2018.
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Human herpesvirus U94A 6A latency transcript expression impairs cytoskeletal function in human nerve cells
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For example, cytoplasmic gelsolin is required for OPC differentiation (Shao et al., 2017) and may play a role in stabilizing the microtubule network during morphological maturation (Liu et al., 2003). Although the mechanism by which this is achieved is unclear, studies in cancer cells have shown that gelsolin can directly interact with β-tubulin and other microtubule-binding proteins such as NAT10 and NuMA-1 (Mazur et al., 2016). Reduced WASF1 function in OPC also results in inhibition of oligodendrocyte maturation and reduction in the number of myelinated axons in vivo.
Many neurodegenerative diseases have a multifactorial etiology and variable course that cannot be explained by current models. Neurotrophic viruses have long been suggested to play a role in these diseases, although their exact involvement remains unclear. Human herpesvirus 6A (HHV-6A) is one of the most commonly detected viruses in the adult brain and has been clinically linked to multiple sclerosis (MS) and more recently to Alzheimer's disease (AD). HHV-6A is a ubiquitous viral pathogen capable of infecting glial cells and neurons. Primary childhood infection is followed by latency induction, characterized by expression of the U94A viral transcript in the absence of viral replication. Here we investigate the effects of U94A on central nervous system cells. We found that U94A expression inhibits migration and impairs cytoplasmic maturation of human oligodendrocyte precursor cells (OPCs) without affecting their viability, a phenotype that may contribute to the failure of remyelination observed in many patients with multiple sclerosis. Subsequent proteomic analysis of U94A-expressing OPCs revealed altered expression of genes involved in tubulin-related regulation of the cytoskeleton. Since HHV-6A appears to be significantly associated with early AD pathology, we extended our initial analysis of the effects of U94A on human-derived neurons. We found that U94A expression suppresses neurite outgrowth in primary human cortical neurons and impairs synaptic maturation. Based on these data, we suggest that the expression of U94A by latent HHV-6A in glial cells and neurons makes them susceptible to dysfunction and degeneration. This is why,latentViral infections of the brain represent a unique pathological risk factor that may contribute to disease processes.
Intracellular partners of fibroblast growth factors 1 and 2 - implications for function
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Excerpt from the quote:
Upregulation of its expression has been correlated with several types of cancer [268-270]. The cytoplasmic gelation-solation transformation of ACTBL2 has been reported to be controlled by gelsolin [271], but Mazur et al. have shown that gelsolin can also be found in the testis [272]. Interestingly, as previously mentioned, we report that gelsolin also interacts with FGF1, indicating the possibility of forming a ternary FGF1-gelsolin-ACTBL2 complex involved in cell growth, cell migration and tumorigenesis.
Fibroblast growth factors 1 and 2 (FGF1 and FGF2) are considered primarily as ligands of surface receptors through which they regulate a wide spectrum of biological processes. They are secreted non-canonically and, unlike other growth factors, are able to move from the endosome to the interior of the cell. These unique features, as well as the role of the intracellular pool of FGF1 and FGF2, are far from fully understood. An increasing number of reports address this issue, focusing on the intracellular interactions of FGF1 and 2. Here, we summarize the current state of knowledge about FGF1 and FGF2 binding partners in the cell and the possible role of these interactions. Partner proteins are grouped according to their function, including proteins involved in secretion, cell signaling, nucleocytoplasmic transport, nucleic acid binding and processing, ATP binding, and cytoskeletal assembly. In-depth network analysis of these binding partners may pinpoint novel, non-classical functions of FGF1 and FGF2 and reveal an additional level of fine-grained control of well-known FGF-regulated cellular processes.
Identification of beta-like actin 2 (ACTBL2) as a novel up-regulated protein in colorectal cancer
2017, Journal of Proteomics
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Current address: Faculty of Science, Department of Experimental Biology, Masaryk University, Czech Republic.
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