scholarly journals Sumoylation regulates the assembly and activity of the SMN complex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Giulietta M. Riboldi ◽  
Irene Faravelli ◽  
Takaaki Kuwajima ◽  
Nicolas Delestrée ◽  
Georgia Dermentzaki ◽  
...  

AbstractSMN is a ubiquitously expressed protein and is essential for life. SMN deficiency causes the neurodegenerative disease spinal muscular atrophy (SMA), the leading genetic cause of infant mortality. SMN interacts with itself and other proteins to form a complex that functions in the assembly of ribonucleoproteins. SMN is modified by SUMO (Small Ubiquitin-like Modifier), but whether sumoylation is required for the functions of SMN that are relevant to SMA pathogenesis is not known. Here, we show that inactivation of a SUMO-interacting motif (SIM) alters SMN sub-cellular distribution, the integrity of its complex, and its function in small nuclear ribonucleoproteins biogenesis. Expression of a SIM-inactivated mutant of SMN in a mouse model of SMA slightly extends survival rate with limited and transient correction of motor deficits. Remarkably, although SIM-inactivated SMN attenuates motor neuron loss and improves neuromuscular junction synapses, it fails to prevent the loss of sensory-motor synapses. These findings suggest that sumoylation is important for proper assembly and function of the SMN complex and that loss of this post-translational modification impairs the ability of SMN to correct selective deficits in the sensory-motor circuit of SMA mice.

2012 ◽  
Vol 445 (3) ◽  
pp. 361-370 ◽  
Author(s):  
Kathryn L. Sarachan ◽  
Kathleen G. Valentine ◽  
Kushol Gupta ◽  
Veronica R. Moorman ◽  
John M. Gledhill ◽  
...  

In humans, assembly of spliceosomal snRNPs (small nuclear ribonucleoproteins) begins in the cytoplasm where the multi-protein SMN (survival of motor neuron) complex mediates the formation of a seven-membered ring of Sm proteins on to a conserved site of the snRNA (small nuclear RNA). The SMN complex contains the SMN protein Gemin2 and several additional Gemins that participate in snRNP biosynthesis. SMN was first identified as the product of a gene found to be deleted or mutated in patients with the neurodegenerative disease SMA (spinal muscular atrophy), the leading genetic cause of infant mortality. In the present study, we report the solution structure of Gemin2 bound to the Gemin2-binding domain of SMN determined by NMR spectroscopy. This complex reveals the structure of Gemin2, how Gemin2 binds to SMN and the roles of conserved SMN residues near the binding interface. Surprisingly, several conserved SMN residues, including the sites of two SMA patient mutations, are not required for binding to Gemin2. Instead, they form a conserved SMN/Gemin2 surface that may be functionally important for snRNP assembly. The SMN–Gemin2 structure explains how Gemin2 is stabilized by SMN and establishes a framework for structure–function studies to investigate snRNP biogenesis as well as biological processes involving Gemin2 that do not involve snRNP assembly.


Author(s):  
А.А. Коваленко ◽  
Г.П. Титова ◽  
В.К. Хугаева

Оперативное лечение различных заболеваний кишечника сопровождается осложнениями в виде нарушений микроциркуляции в области анастомоза кишки. Ранее нами показана способность лимфостимуляторов пептидной природы восстанавливать нарушенную микроциркуляцию, что послужило основой для настоящего исследования. Цель работы - оценка влияния стимуляции лимфотока в стенке кишки на процессы восстановления микроциркуляции, структуры и функции тонкой кишки в области оперативного вмешательства. Методика. В экспериментах на наркотизированных крысах (хлоралгидрат в дозе 0,6 г/кг в 0,9% растворе NaCl) моделировали различные поражения тонкой кишки (наложение лигатуры, перевязка 1-3 брыжеечных артерий, перекрут петли кишки вокруг оси брыжейки, сочетание нескольких видов повреждений). Резекция поврежденного участка через 1 сут. с последующим созданием тонкокишечного анастомоза завершалась орошением операционного поля раствором пептида-стимулятора лимфотока (40 мкг/кг массы животного в 1 мл 0,9% раствора NaCl). На 7-е сут. после операции проводили гистологическое исследование фрагмента кишки в области анастомоза. Результаты. На 7-е сут. после резекции у выживших животных (летальность вследствие кишечной непроходимости составляла 30%) имеют место морфологические признаки острых сосудистых нарушений стенки кишки, изменений кровеносных и лимфатических микрососудов, интерстициальный отек всех слоев стенки кишки, дилатация просвета кишки, повреждение всасывающего эпителия ворсин с истончением щеточной каемки клеток, морфологические признаки гиперфункции бокаловидных клеток. Использование лимфостимулятора пептидной природы после операции увеличивало выживаемость животных на 24%. У части животных отмечалось уменьшение расширения просвета кишки, у других практически полная его нормализация. Восстанавливалась форма кишечных ворсин и распределение бокаловидных клеток. Отсутствовали признаки внутриклеточного и межмышечного отека. Отмечено умеренное полнокровие венул. Заключение. Использование лимфостимулятора при хирургическом лечении кишечной непроходимости увеличивает выживаемость животных на 24% по сравнению с контролем, способствует более раннему восстановлению структуры и функции тонкой кишки. Полученные результаты свидетельствуют о перспективности использования стимуляции лимфотока при операциях на кишечнике. Surgical treatment of bowel diseases is associated with complications that cause microcirculatory disturbances in the anastomosis area and may lead to a fatal outcome. This study was based on our previous finding that peptide-type lymphatic stimulators are able to restore impaired microcirculation. The aim of this work was stimulating the lymph flow in the intestinal wall to facilitate recovery of microcirculation, structure and function of the small intestine in the area of surgical intervention. Methods. In experiments on anesthetized rats (0.6 g/kg chloral hydrate in 0.9% NaCl), various small bowel lesions were modeled (bowel ligation, ligation of 1-3 mesenteric arteries, gut torsion, combination of several lesion types). In 24 h, the damaged area was resected, and a small intestine anastomosis was creased. The surgery was completed with irrigation of the operative field with a solution of lymph flow stimulating peptide (40 мg/kg body weight in 1 ml of 0.9% NaCl). A gut fragment from the anastomosis area was examined histologically on day 7 after the surgery. Results. On the 7th day after removing the intestinal obstruction, the surviving animals (lethality 30%) had morphological signs of acute vascular disorders in the intestinal wall; changes in blood and lymphatic microvessels; interstitial edema of all intestinal wall layers; dilatation of the intestinal lumen; damage to the absorptive epithelium of villi with thinning of the brush border, and hyperfunction of mucous (goblet) cells. The use of the peptide after surgery increased the survival rate of animals by 24% and provided a smaller dilatation of the intestinal lumen in some animals. In other animals, the lumen recovered. The shape of intestinal villi and distribution of goblet cells were restored. Signs of intracellular and intermuscular edema were absent. Moderate venular congestion was noticed. Conclusion. Using the lymphatic stimulator in surgical treatment of intestinal obstruction increases the survival rate of animals by 24% compared to the control, facilitates earlier restoration of the small intestine structure and function. The obtained results indicated the effectiveness of lymphatic stimulation in intestinal surgery.


2020 ◽  
Vol 25 (43) ◽  
pp. 4560-4569 ◽  
Author(s):  
Yichen Lee ◽  
Bo H. Lee ◽  
William Yip ◽  
Pingchen Chou ◽  
Bak-Sau Yip

Neurofilaments: light, medium, and heavy (abbreviated as NF-L, NF-M, and NF-H, respectively), which belong to Type IV intermediate filament family (IF), are neuron-specific cytoskeletal components. Neurofilaments are axonal structural components and integral components of synapses, which are important for neuronal electric signal transmissions along the axons and post-translational modification. Abnormal assembly of neurofilaments is found in several human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy (SMA), and hereditary sensory-motor neuropathy (HSMN). In addition, those pathological neurofilament accumulations are known in α-synuclein in Parkinson’s disease (PD), Aβ and tau in Alzheimer’s disease (AD), polyglutamine in CAG trinucleotide repeat disorders, superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP43), neuronal FUS proteins, optineurin (OPTN), ubiquilin 2 (UBQLN2), and dipeptide repeat protein (DRP) in amyotrophic lateral sclerosis (ALS). When axon damage occurs in central nervous disorders, neurofilament proteins are released and delivered into cerebrospinal fluid (CSF), which are then circulated into blood. New quantitative analyses and assay techniques are well-developed for the detection of neurofilament proteins, particularly NF-L and the phosphorylated NF-H (pNF-H) in CSF and serum. This review discusses the potential of using peripheral blood NF quantities and evaluating the severity of damage in the nervous system. Intermediate filaments could be promising biomarkers for evaluating disease progression in different nervous system disorders.


2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 491.2-491
Author(s):  
M. Tada ◽  
Y. Yamada ◽  
K. Mandai ◽  
N. Hidaka

Background:We previously reported that the prevalence of sarcopenia was 28% in patients with rheumatoid arthritis (RA) in a cohort study 1. RA patients have a high risk of falls and fractures 2. However, the predictors of falls and fractures in RA patients are not known.Objectives:Whether evaluation of muscle mass and function at baseline could predict falls and fractures during four-year follow-up was investigated.Methods:The four-year follow-up data from a prospective, observational study (CHIKARA study: Correlation researcH of sarcopenIa, sKeletal muscle and disease Activity in Rheumatoid Arthritis) were used. Muscle mass was measured by a body impedance analyzer, and leg muscle mass was calculated. The leg muscle score (max: 100, min: 0) reflected the ratio of leg muscle mass to overall weight. Grip strength as an indicator of muscle function was evaluated using a digital, hand-held, isokinetic dynamometer. The correlations between muscle mass or function and falls or fractures were analyzed by survival rates and Cox hazard ratios. Leg muscle mass and grip strength were investigated by receiver operating characteristic (ROC) curve analysis for correlations with falls or fractures.Results:A total of 100 RA patients (female: 78%, mean age: 66.1 years) were enrolled; 35 patients had falls, and 19 patients had fractures during the four-year follow-up. The leg muscle score, grip strength, age, and fractures at baseline were significantly correlated with falls. The cut-off values of the leg muscle score and grip strength were calculated to be 84.5 points (sensitivity: 0.79, specificity: 0.43) and 15.9 kg (sensitivity: 0.56, specificity: 0.70), respectively, by ROC curve analysis. The patients were divided into four groups by their leg muscle scores and grip strength; the numbers of falls and fractures are shown in Table 1 for each group. The fall-free survival rate was significantly lower in the group with low leg muscle score and low grip strength (35.3%) than in the other groups (P=0.002) (Figure 1). The hazard ratio for the both low group was significantly increased, 3.6-fold (95%CI: 1.1-11.5), compared to that in the both high group.Table 1.Numbers of falls and fractures by category of leg muscle score and grip strengthLG + GS+(n=34)LG - GS+(n=12)LG + GS-(n=37)LG - GS-(n=17)P value*Falls, N6515110.010Fractures, N34660.072LG+: leg muscle score >84.5 points, GS+: grip strength >15.9kg, LG-: leg muscle score ≤84.5 points, GS+: grip strength ≤15.9kg*: compared in four groups by Kruskal-Walls test.Figure 1.Fall-free survival rate in the four groupsConclusion:RA patients with both low leg muscle score and low grip strength at baseline were at high risk for falls during the four-year follow-up period. Evaluation of muscle mass and function can predict falls in RA patients.References:[1]Tada, M., Yamada, Y., Mandai, K. & Hidaka, N. Matrix metalloprotease 3 is associated with sarcopenia in rheumatoid arthritis - results from the CHIKARA study. Int J Rheum Dis21, 1962-1969, doi:10.1111/1756-185X.13335 (2018).[2]van Staa, T. P., Geusens, P., Bijlsma, J. W., Leufkens, H. G. & Cooper, C. Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum54, 3104-3112, doi:10.1002/art.22117 (2006).Disclosure of Interests:None declared


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chao Gao ◽  
Chong Ma ◽  
Huqiang Wang ◽  
Haolin Zhong ◽  
Jiayin Zang ◽  
...  

AbstractInterestingly, some protein domains are intrinsically disordered (abbreviated as IDD), and the disorder degree of same domains may differ in different contexts. However, the evolutionary causes and biological significance of these phenomena are unclear. Here, we address these issues by genome-wide analyses of the evolutionary and functional features of IDDs in 1,870 species across the three superkingdoms. As the result, there is a significant positive correlation between the proportion of IDDs and organism complexity with some interesting exceptions. These phenomena may be due to the high disorder of clade-specific domains and the different disorder degrees of the domains shared in different clades. The functions of IDDs are clade-specific and the higher proportion of post-translational modification sites may contribute to their complex functions. Compared with metazoans, fungi have more IDDs with a consecutive disorder region but a low disorder ratio, which reflects their different functional requirements. As for disorder variation, it’s greater for domains among different proteins than those within the same proteins. Some clade-specific ‘no-variation’ or ‘high-variation’ domains are involved in clade-specific functions. In sum, intrinsic domain disorder is related to both the organism complexity and clade-specific functions. These results deepen the understanding of the evolution and function of IDDs.


2008 ◽  
Vol 29 (5) ◽  
pp. 1107-1115 ◽  
Author(s):  
Barrington G. Burnett ◽  
Eric Muñoz ◽  
Animesh Tandon ◽  
Deborah Y. Kwon ◽  
Charlotte J. Sumner ◽  
...  

ABSTRACT Spinal muscular atrophy (SMA) is caused by mutations of the survival of motor neuron (SMN1) gene and deficiency of full-length SMN protein (FL-SMN). All SMA patients retain one or more copies of the SMN2 gene, but the principal protein product of SMN2 lacks exon 7 (SMNΔ7) and is unable to compensate for a deficiency of FL-SMN. SMN is known to oligomerize and form a multimeric protein complex; however, the mechanisms regulating stability and degradation of FL-SMN and SMNΔ7 proteins have been largely unexplored. Using pulse-chase analysis, we characterized SMN protein turnover and confirmed that SMN was ubiquitinated and degraded by the ubiquitin proteasome system (UPS). The SMNΔ7 protein had a twofold shorter half-life than FL-SMN in cells despite similar intrinsic rates of turnover by the UPS in a cell-free assay. Mutations that inhibited SMN oligomerization and complex formation reduced the FL-SMN half-life. Furthermore, recruitment of SMN into large macromolecular complexes as well as increased association with several Gemin proteins was regulated in part by protein kinase A. Together, our data indicate that SMN protein stability is modulated by complex formation. Promotion of the SMN complex formation may be an important novel therapeutic strategy for SMA.


2017 ◽  
Vol 5 (12) ◽  
pp. e13290 ◽  
Author(s):  
Anne Hahn ◽  
Johannes Faulhaber ◽  
Lalita Srisawang ◽  
Andreas Stortz ◽  
Johanna J Salomon ◽  
...  

2020 ◽  
Author(s):  
Qian Dong ◽  
Michael Zavortink ◽  
Francesca Froldi ◽  
Sofya Golenkina ◽  
Tammy Lam ◽  
...  

AbstractThe final size and function of the adult central nervous system (CNS) is determined by neuronal lineages generated by neural stem cells (NSCs) in the developing brain. In Drosophila, NSCs called neuroblasts (NBs) reside within a specialised microenvironment called the glial niche. Here, we explore non-autonomous glial regulation of NB proliferation. We show that lipid droplets (LDs) which reside within the glial niche are closely associated with the signalling molecule Hedgehog (Hh). Under physiological conditions, cortex glial Hh is autonomously required to sustain niche chamber formation, and non-autonomously restrained to prevent ectopic Hh signalling in the NBs. In the context of cortex glial overgrowth, induced by Fibroblast Growth Factor (FGF) activation, Hh and lipid storage regulators Lsd-2 and Fasn1 were upregulated, resulting in activation of Hh signalling in the NBs; which in turn disrupted NB cell cycle progression and reduced neuronal production. We show that the LD regulator Lsd-2 modulates Hh’s ability to signal to NBs, and de novo lipogenesis gene Fasn1 regulates Hh post-translational modification via palmitoylation. Together, our data suggest that the glial niche non-autonomously regulates NB proliferation and neural lineage size via Hh signaling that is modulated by lipid metabolism genes.


2021 ◽  
Vol 22 (19) ◽  
pp. 10677
Author(s):  
Huqiang Wang ◽  
Haolin Zhong ◽  
Chao Gao ◽  
Jiayin Zang ◽  
Dong Yang

The consecutive disordered regions (CDRs) are the basis for the formation of intrinsically disordered proteins, which contribute to various biological functions and increasing organism complexity. Previous studies have revealed that CDRs may be present inside or outside protein domains, but a comprehensive analysis of the property differences between these two types of CDRs and the proteins containing them is lacking. In this study, we investigated this issue from three viewpoints. Firstly, we found that in-domain CDRs are more hydrophilic and stable but have less stickiness and fewer post-translational modification sites compared with out-domain CDRs. Secondly, at the protein level, we found that proteins with only in-domain CDRs originated late, evolved rapidly, and had weak functional constraints, compared with the other two types of CDR-containing proteins. Proteins with only in-domain CDRs tend to be expressed spatiotemporal specifically, but they tend to have higher abundance and are more stable. Thirdly, we screened the CDR-containing protein domains that have a strong correlation with organism complexity. The CDR-containing domains tend to be evolutionarily young, or they changed from a domain without CDR to a CDR-containing domain during evolution. These results provide valuable new insights about the evolution and function of CDRs and protein domains.


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