scholarly journals SIRT7-Induced PHF5A Decrotonylation Regulates Aging Progress Through Alternative Splicing-Mediated Downregulation of CDK2

2021 ◽  
Vol 9 ◽  
Author(s):  
Ai Qing Yu ◽  
Jie Wang ◽  
Shi Tao Jiang ◽  
Li Qun Yuan ◽  
Hai Yan Ma ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Posttranslational Modification ◽  
Cellular Aging ◽  
Sperm Development ◽  
New Ideas ◽  
Dependent Protein ◽  
Modern Mass ◽  
Protein Deacetylase ◽  
Cdk2 Expression

Dysregulation of protein posttranslational modification (PTM) can lead to a variety of pathological processes, such as abnormal sperm development, malignant tumorigenesis, depression, and aging process. SIRT7 is a NAD+-dependent protein deacetylase. Besides known deacetylation, SIRT7 may also have the capacity to remove other acylation. However, the roles of SIRT7-induced other deacylation in aging are still largely unknown. Here, we found that the expression of SIRT7 was significantly increased in senescent fibroblasts and aged tissues. Knockdown or overexpression of SIRT7 can inhibit or promote fibroblast senescence. Knockdown of SIRT7 led to increased pan-lysine crotonylation (Kcr) levels in senescent fibroblasts. Using modern mass spectrometry (MS) technology, we identified 5,149 Kcr sites across 1,541 proteins in senescent fibroblasts, and providing the largest crotonylome dataset to date in senescent cells. Specifically, among the identified proteins, we found SIRT7 decrotonylated PHF5A, an alternative splicing (AS) factor, at K25. Decrotonylation of PHF5A K25 contributed to decreased CDK2 expression by retained intron (RI)-induced abnormal AS, thereby accelerating fibroblast senescence, and supporting a key role of PHF5A K25 decrotonylation in aging. Collectively, our data revealed the molecular mechanism of SIRT7-induced k25 decrotonylation of PHF5A regulating aging and provide new ideas and molecular targets for drug intervention in cellular aging and the treatment of aging-related diseases, and indicating that protein crotonylation has important implications in the regulation of aging progress.

scholarly journals SIRT7 is a deacetylase of N4-acetylcytidine on ribosomal RNA

2021 ◽  
Author(s):  
Chenzhong Xu ◽  
Jin Zhang ◽  
Jie Zhang ◽  
Baohua Liu
Keyword(s):  
Circadian Rhythms ◽  
Ribosomal Rna ◽  
Genome Stability ◽  
Rna Stability ◽  
Translation Efficiency ◽  
Dependent Protein ◽  
First Time ◽  
Protein Deacetylase

AbstractN-acetyltransferase 10 catalyzes RNA N4-acetylcytidine (ac4C) modifications and thus regulates RNA stability and translation efficiency. However, the deacetylase for ac4C is unknown. SIRT7 was initially identified as an NAD+-dependent protein deacetylase and plays essential roles in genome stability, circadian rhythms, metabolism, and aging. In this study, we identified SIRT7 as a deacetylase of the ac4C of ribosomal (r)RNA for the first time and found it to be NAD+-independent. Our data highlight the important role of SIRT7 in rRNA ac4C modification and suggest an additional epitranscriptional regulation of aging.

scholarly journals CaMKIIβ Association with the Actin Cytoskeleton Is Regulated by Alternative Splicing

2006 ◽  
Vol 17 (11) ◽  
pp. 4656-4665 ◽  
Author(s):  
Heather O'Leary ◽  
Erika Lasda ◽  
K. Ulrich Bayer
Keyword(s):  
Skeletal Muscle ◽  
Nervous System ◽  
Alternative Splicing ◽  
Actin Cytoskeleton ◽  
Actin Filaments ◽  
Kinase Activity ◽  
Dependent Protein Kinase ◽  
Dependent Protein

The Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII)β has morphogenic functions in neurons not shared by the α isoform. CaMKIIβ contains three exons (v1, v3, and v4) not present in the CaMKIIα gene, and two of these exons (v1 and v4) are subject to differential alternative splicing. We show here that CaMKIIβ, but not α, mediated bundling of F-actin filaments in vitro. Most importantly, inclusion of exon v1 was required for CaMKIIβ association with the F-actin cytoskeleton within cells. CaMKIIβe, which is the dominant variant around birth and lacks exon v1 sequences, failed to associate with F-actin. By contrast, CaMKIIβ′, which instead lacks exon v4, associated with F-actin as full-length CaMKIIβ. Previous studies with CaMKIIβ mutants have indicated a role of nonstimulated kinase activity in enhancing dendritic arborization. Here, we show that F-actin–targeted CaMKIIβ, but not α, was able to phosphorylate actin in vitro even by nonstimulated basal activity in absence of Ca2+/CaM. In rat pancreatic islets and in skeletal muscle, the actin-associated CaMKIIβ′ and βM were the predominant variants, respectively. Thus, cytoskeletal targeting may mediate functions of CaMKIIβ variants also outside the nervous system.

scholarly journals In Vivo Selection of Kinase-responsive RNA Elements Controlling Alternative Splicing

2009 ◽  
Vol 284 (24) ◽  
pp. 16191-16201 ◽  
Author(s):  
Hongzhao Li ◽  
Guodong Liu ◽  
Jiankun Yu ◽  
Wenguang Cao ◽  
Vincent G. Lobo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Protein Kinase ◽  
Cultured Cells ◽  
Feedback Regulation ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Rna Elements ◽  
Cell Signals

Alternative pre-mRNA splicing is often controlled by cell signals, for example, those activating the cAMP-dependent protein kinase (PKA) or the Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). We have shown that CaMKIV regulates alternative splicing through short CA repeats and hnRNP L. Here we use a splicing reporter that shows PKA/CaMKIV promotion of exon inclusion to select from exons containing random 13-nt sequences for RNA elements responsive to the kinases in cultured cells. This selection not only identified both PKA- and CaMKIV-responsive elements that are similar to the CaMKIV-responsive RNA element 1 (CaRRE1) or CA repeats, but also A-rich elements not previously known to respond to these kinases. Consistently, hnRNP L is identified as a factor binding the CA-rich elements. Analyses of the motifs in the highly responsive elements indicate that they are indeed critical for the kinase effect and are enriched in alternative exons. Interestingly, a CAAAAAA motif is sufficient for the PKA/CaMKIV-regulated splicing of the exon 16 of the CaMK kinase β1 (CaMKK2) transcripts, implying a role of this motif in signaling cross-talk or feedback regulation between these kinases through alternative splicing. Therefore, these experiments identified a group of RNA elements responsive to PKA and CaMKIV from in vivo selection. This also provides an approach for selecting RNA elements similarly responsive to other cell signals controlling alternative splicing.

PP1γ functionally augments the alternative splicing of CaMKIIδ through interaction with ASF

2014 ◽  
Vol 306 (2) ◽  
pp. C167-C177 ◽  
Author(s):  
Chao Huang ◽  
Wenwen Cao ◽  
Rujia Liao ◽  
Jia Wang ◽  
Yuzhe Wang ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Protein Kinase ◽  
Specific Inhibitor ◽  
Glucose Deprivation ◽  
Structural Analog ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Heart Disorders ◽  
Alternative Splicing Factor

Protein phosphatase 1 (PP1) and Ca2+/calmodulin-dependent protein kinase δ (CaMKIIδ) are upregulated in heart disorders. Alternative splicing factor (ASF), a major splice factor for CaMKIIδ splicing, can be regulated by both protein kinase and phosphatase. Here we determine the role of PP1 isoforms in ASF-mediated splicing of CaMKIIδ in cells. We found that 1) PP1γ, but not α or β isoform, enhanced the splicing of CaMKIIδ in HEK293T cells; 2) PP1γ promoted the function of ASF, evidenced by the existence of ASF-PP1γ association as well as the PP1γ overexpression- or silencing-mediated change in CaMKIIδ splicing in ASF-transfected HEK293T cells; 3) CaMKIIδ splicing was promoted by overexpression of PP1γ and impaired by application of PP1 inhibitor 1 (I1PP1) or pharmacological inhibitor tautomycetin in primary cardiomyocytes; 4) CaMKIIδ splicing and enhancement of ASF-PP1γ association induced by oxygen-glucose deprivation followed by reperfusion (OGD/R) were potentiated by overexpression of PP1γ and suppressed by inhibition of PP1γ with I1PP1 or tautomycetin in primary cardiomyocytes; 5) functionally, overexpression and inhibition of PP1γ, respectively, potentiated or suppressed the apoptosis and Bax/Bcl-2 ratio, which were associated with the enhanced activity of CaMKII in OGD/R-stimulated cardiomyocytes; and 6) CaMKII was required for the OGD/R induced- and PP1γ exacerbated-apoptosis of cardiomyocytes, evidenced by a specific inhibitor of CaMKII KN93, but not its structural analog KN92, attenuating the apoptosis and Bax/Bcl-2 ratio in OGD/R and PP1γ-treated cells. In conclusion, our results show that PP1γ promotes the alternative splicing of CaMKIIδ through its interacting with ASF, exacerbating OGD/R-triggered apoptosis in primary cardiomyocytes.

scholarly journals PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Dawei Chen ◽  
Zhenguo Zhao ◽  
Lu Chen ◽  
Qinghua Li ◽  
Jixue Zou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Alternative Splicing ◽  
Protein Function ◽  
Vital Role ◽  
Normal Tissues ◽  
Mechanistic Analysis ◽  
Highly Correlated ◽  
Splicing Patterns

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

scholarly journals LncRNA CRNDE attenuates chemoresistance in gastric cancer via SRSF6-regulated alternative splicing of PICALM

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Feifei Zhang ◽  
Hui Wang ◽  
Jiang Yu ◽  
Xueqing Yao ◽  
Shibin Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Alternative Splicing ◽  
Noncoding Rna ◽  
De Novo ◽  
Acquired Resistance ◽  
Genetic Alterations ◽  
Clinical Samples ◽  
Autophagy Flux ◽  
Resistance To Chemotherapy

AbstractDe novo and acquired resistance, which are mainly mediated by genetic alterations, are barriers to effective routine chemotherapy. However, the mechanisms underlying gastric cancer (GC) resistance to chemotherapy are still unclear. We showed that the long noncoding RNA CRNDE was related to the chemosensitivity of GC in clinical samples and a PDX model. CRNDE was decreased and inhibited autophagy flux in chemoresistant GC cells. CRNDE directly bound to splicing protein SRSF6 to reduce its protein stability and thus regulate alternative splicing (AS) events. We determined that SRSF6 regulated the PICALM exon 14 skip splice variant and triggered a significant S-to-L isoform switch, which contributed to the expression of the long isoform of PICALM (encoding PICALML). Collectively, our findings reveal the key role of CRNDE in autophagy regulation, highlighting the significance of CRNDE as a potential prognostic marker and therapeutic target against chemoresistance in GC.

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