Epigenetic activation of secretory phenotypes in senescence by the FOXQ1-SIRT4-GDH signaling.

Although metabolic reprogramming is characterized as a hallmark of aging, implications of the crucial glutamate dehydrogenase (GDH) in human senescence remain poorly understood. Here, we report that GDH activity is significantly increased in aged mice and senescent human diploid fibroblasts. This enzymatic potentiation is associated with de-repression of GDH from its functionally suppressive ADP-ribosylation modification catalyzed by NAD-dependent ADP-ribosyltransferase/deacetylase SIRT4. A series of transcription analyses led to the identification of FOXQ1, a forkhead family transcription factor (TF), responsible for the maintenance of SIRT4 expression levels in juvenile cells. However, this metabolically balanced FOXQ1-SIRT4-GDH axis, is shifted in senescence with gradually decreasing expressions of FOXQ1 and SIRT4 and elevated GDH activity. Importantly, pharmaceutical inhibition of GDH suppresses the aberrantly activated transcription of IL-6 and IL-8, two major players in senescence-associated secretory phenotype (SASP), and this action is mechanistically associated with erasure of the repressive H3K9me3 (trimethylation of lysine 9 on histone H3) marks at IL-6 and IL-8 promoters, owing to the requirement of α-ketoglutaric acid (α-KG) from GDH-mediated glutamate dehydrogenase reaction as a cofactor for histone demethylation. In supplement with the phenotypic evidence from FOXQ1/SIRT4/GDH manipulations, these data support the integration of metabolism alterations and epigenetic regulation in driving senescence progression and highlight the FOXQ1-SIRT4-GDH axis as a novel druggable target for improving human longevity.

RSL1D1 modulates cell senescence and proliferation via regulation of PPARγ mRNA stability.

AIMS: In this study, we will examine if RSL1D1 influences PPARγ expression and explore the underlying mechanism that RSL1D1 regulates PPARγ expression. Moreover, the significance of RSL1D1-PPARγ pathway in cell senescence and proliferation will also be determined. MAIN METHODS: Our main methods include western blotting, immunoprecipitation (IP), real-time PCR, RNA Immunoprecipitation (RIP), biotin-labeled RNA pull down assay, dual luciferase reporter gene assay, senescence-associated ß-galactosidase staining, cell proliferation assay, colony formation assay, wound healing assay, blood biochemistry test and Oil red O staining. KEY FINDINGS: By analyzing gene chip results we find that the expression of RSL1D1 and PPARγ might be correlated. Then we show that RSL1D1 is a posttranscriptional regulator of PPARγ. RSL1D1 overexpression elevates, while RSL1D1 knockdown inhibits, PPARγ mRNA and protein expression levels. Mechanistically, we find that RSL1D1 directly interacts with the 3'-untranslated region of PPARγ mRNA, and then promotes its stability and increases PPARγ protein expression level. We further demonstrate that RSL1D1 modulates cellular senescence and cell proliferation partially via PPARγ-regulated downstream target genes such as PTEN/p27, NF-κB, GLUT4, and ACL. Moreover, we find that RSL1D1 regulates PPARγ expression and function in a HuR-dependent manner. Last, we show that RSL1D1 knockout in mouse adipose tissue shortens mouse lifespan and leads to hepatic damage which may impair liver damage repair function. SIGNIFICANCE: Collectively, our findings unveil a novel posttranscriptional regulation of PPARγ by RSL1D1 and uncover a critical role of RSL1D1-PPARγ-PPARγ downstream target genes in regulating cellular senescence and cell proliferation.

CRL4DCAF8 dependent opposing stability control over the chromatin remodeler LSH orchestrates epigenetic dynamics in ferroptosis.

Despite the emerging evidence on ferroptosis implicated in diverse pathologies, molecular linkage between oxidative inducers and chromatin as epigenetic memory carrier for its propagation remains elusive. Here, we report the identification of two WD40 proteins DCAF8 and WDR76 as substrate adapter and molecular inhibitor respectively of the Cullin-4 RING ubiquitin ligase (CRL4) system for stability control of chromatin remodeler LSH. Degradation analysis and CRL4-DCAF8 complex reconstitution demonstrate that CRL4DCAF8 is a bona fide E3 ligase for LSH. In contrast, WDR76 antagonizes DCAF8-targeted LSH proteolysis through competitive inhibition of the holo-CRL4DCAF8-LSH complex assembly. Importantly, this opposing regulatory strategy is utilized in lipid hydroperoxide induced ferroptosis, where we identify key redox homeostasis genes significantly regulated by the DCAF8/WDR76/LSH axis through transcriptomic epistasis analysis. This regulation is mechanistically attributed to DNA hydroxymethylation fostered WDR76 interaction with LSH and increased ratio of DCAF8 to WDR76 for antagonistic LSH association accompanying decreased DNA oxidation along with ROS overproduction. Evaluation of epigenetic dynamics at ferroptosis gene promoters reveals linker histone H1- and LSH-associated transcriptional repression is coordinately removed upon lipid peroxidation stress. Together with the phenotypes driven by WDR76 and DCAF8 manipulations, these data identify DCAF8- and WDR76-adapted oxidative damage sensing through DNA hydroxymethylation for LSH degradation control as a crucial nexus in epigenetic regulation of ferroptosis.

Protein kinase D1 phosphorylation of KAT7 enhances its protein stability and promotes replication licensing and cell proliferation.

The histone acetyltransferase (HAT) KAT7/HBO1/MYST2 plays a crucial role in the pre-replication complex (pre-RC) formation, DNA replication and cell proliferation via acetylation of histone H4 and H3. In a search for protein kinase D1 (PKD1)-interacting proteins, we have identified KAT7 as a potential PKD1 substrate. We show that PKD1 directly interacts and phosphorylates KAT7 at Thr97 and Thr331 in vitro and in vivo. PKD1-mediated phosphorylation of KAT7 enhances its expression levels and stability by reducing its ubiquitination-mediated degradation. Significantly, the phospho-defective mutant KAT7-Thr97/331A attenuates histone H4 acetylation levels, MCM2/6 loading on the chromatin, DNA replication and cell proliferation. Similarly, PKD1 knockdown decreases, whereas the constitutive active mutant PKD1-CA increases histone H4 acetylation levels and MCM2/6 loading on the chromatin. Overall, these results suggest that PKD1-mediated phosphorylation of KAT7 may be required for pre-RC formation and DNA replication.

A research agenda for ageing in China in the 21st century (2nd edition): Focusing on basic and translational research, long-term care, policy and social networks.

One of the key issues facing public healthcare is the global trend of an increasingly ageing society which continues to present policy makers and caregivers with formidable healthcare and socio-economic challenges. Ageing is the primary contributor to a broad spectrum of chronic disorders all associated with a lower quality of life in the elderly. In 2019, the Chinese population constituted 18 % of the world population, with 164.5 million Chinese citizens aged 65 and above (65+), and 26 million aged 80 or above (80+). China has become an ageing society, and as it continues to age it will continue to exacerbate the burden borne by current family and public healthcare systems. Major healthcare challenges involved with caring for the elderly in China include the management of chronic non-communicable diseases (CNCDs), physical frailty, neurodegenerative diseases, cardiovascular diseases, with emerging challenges such as providing sufficient dental care, combating the rising prevalence of sexually transmitted diseases among nursing home communities, providing support for increased incidences of immune diseases, and the growing necessity to provide palliative care for the elderly. At the governmental level, it is necessary to make long-term strategic plans to respond to the pressures of an ageing society, especially to establish a nationwide, affordable, annual health check system to facilitate early diagnosis and provide access to affordable treatments. China has begun work on several activities to address these issues including the recent completion of the of the Ten-year Health-Care Reform project, the implementation of the Healthy China 2030 Action Plan, and the opening of the National Clinical Research Center for Geriatric Disorders. There are also societal challenges, namely the shift from an extended family system in which the younger provide home care for their elderly family members, to the current trend in which young people are increasingly migrating towards major cities for work, increasing reliance on nursing homes to compensate, especially following the outcomes of the 'one child policy' and the 'empty-nest elderly' phenomenon. At the individual level, it is important to provide avenues for people to seek and improve their own knowledge of health and disease, to encourage them to seek medical check-ups to prevent/manage illness, and to find ways to promote modifiable health-related behaviors (social activity, exercise, healthy diets, reasonable diet supplements) to enable healthier, happier, longer, and more productive lives in the elderly. Finally, at the technological or treatment level, there is a focus on modern technologies to counteract the negative effects of ageing. Researchers are striving to produce drugs that can mimic the effects of 'exercising more, eating less', while other anti-ageing molecules from molecular gerontologists could help to improve 'healthspan' in the elderly. Machine learning, 'Big Data', and other novel technologies can also be used to monitor disease patterns at the population level and may be used to inform policy design in the future. Collectively, synergies across disciplines on policies, geriatric care, drug development, personal awareness, the use of big data, machine learning and personalized medicine will transform China into a country that enables the most for its elderly, maximizing and celebrating their longevity in the coming decades. This is the 2nd edition of the review paper (Fang EF et al., Ageing Re. Rev. 2015).

Sirtuins and their Biological Relevance in Aging and Age-Related Diseases.

Sirtuins, initially described as histone deacetylases and gene silencers in yeast, are now known to have many more functions and to be much more abundant in living organisms. The increasing evidence of sirtuins in the field of ageing and age-related diseases indicates that they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. Here, we summarize some of the recent discoveries in sirtuin biology that clearly implicate the functions of sirtuins in the regulation of aging and age-related diseases. Furthermore, human sirtuins are considered promising therapeutic targets for anti-aging and ageing-related diseases and have attracted interest in scientific communities to develop small molecule activators or drugs to ameliorate a wide range of ageing disorders. In this review, we also summarize the discovery and development status of sirtuin-targeted drug and further discuss the potential medical strategies of sirtuins in delaying aging and treating age-related diseases.

OTUD5 cooperates with TRIM25 in transcriptional regulation and tumor progression via deubiquitination activity.

Oncogenic processes exert their greatest effect by targeting regulators of cell proliferation. Studying the mechanism underlying growth augmentation is expected to improve clinical therapies. The ovarian tumor (OTU) subfamily deubiquitinases have been implicated in the regulation of critical cell-signaling cascades, but most OTUs functions remain to be investigated. Through an unbiased RNAi screen, knockdown of OTUD5 is shown to significantly accelerate cell growth. Further investigation reveals that OTUD5 depletion leads to the enhanced transcriptional activity of TRIM25 and the inhibited expression of PML by altering the ubiquitination level of TRIM25. Importantly, OTUD5 knockdown accelerates tumor growth in a nude mouse model. OTUD5 expression is markedly downregulated in tumor tissues. The reduced OTUD5 level is associated with an aggressive phenotype and a poor clinical outcome for cancers patients. Our findings reveal a mechanism whereby OTUD5 regulates gene transcription and suppresses tumorigenesis by deubiquitinating TRIM25, providing a potential target for oncotherapy.

CRL4DCAF8 and USP11 oppositely regulate the stability of myeloid leukemia factors (MLFs).

Myeloid leukemia factors (MLF1 and MLF2) are proteins associated with leukemia and several other cancers. However, little is known about the regulatory mechanisms underlying the stability of these proteins. Here, we show that DDB1 and CUL4 associated factor 8 (DCAF8), which can form a functional E3 ligase complex (CRL4DCAF8), has a strong interaction with the MLF2 protein. DCAF8 could promote MLF2 degradation through the ubiquitin-proteasome pathway. In contrast, ubiquitin specific peptidase 11 (USP11) associates with MLF2, thereby increasing its stability. Since MLF1 is highly related to MLF2, we demonstrated that MLF1 also interacts with DCAF8 and USP11, suggesting that CRL4DCAF8 and USP11 may also regulate the expression of MLF1. TCGA analysis revealed that both the myeloid leukemia factors (MLF1 and MLF2) show significant differential expression in various tumors. The results of our study indicate that CRL4DCAF8 and USP11 play opposite roles in the regulation of MLF1 and MLF2, which may, in turn, affect their biological functions in various cancers.

HnRNP F/H associate with hTERC and telomerase holoenzyme to modulate telomerase function and promote cell proliferation.

Human telomerase RNA component hTERC comprises multiple motifs that contribute to hTERC biogenesis, holoenzyme activity, and enzyme recruitment to telomeres. hTERC contains several guanine tracts (G-tracts) at its 5'-end, but its associated proteins and potential roles in telomerase function are still poorly understood. The heterogeneous nuclear ribonucleoproteins F, H1, and H2 (hnRNP F/H) are splicing factors that preferentially bind to poly(G)-rich sequences RNA. Here, we demonstrate that hnRNP F/H associate with both hTERC and telomerase holoenzyme to regulate telomerase activity. We reveal hnRNP F/H bind to the 5'-end region of hTERC in vitro and in vivo, and identify the first three G-tracts of hTERC and qRRM1 domain of hnRNP F/H are required for their interaction. Furthermore, hnRNP F/H also directly interact with telomerase holoenzyme. Functionally, we show that hnRNP F/H plays important roles in modulating telomerase activity and telomere length. Moreover, hnRNP F/H deletion greatly impair cancer and stem cell proliferation, and induce stem cell senescence, while hnRNP F/H overexpression delay stem cell senescence. Collectively, our findings unveil a novel role of hnRNP F/H as the binding partners of hTERC and telomerase holoenzyme to regulate telomerase function.

lncRNA miat functions as a ceRNA to upregulate sirt1 by sponging miR-22-3p in HCC cellular senescence.

Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths and lacks effective therapies. Cellular senescence acts as a barrier against cancer progression and plays an important role in tumor suppression. Senescence associated long noncoding RNAs (SAL-RNAs) are thought to be critical regulators of cancer development. Here, the long noncoding RNA (lncRNA) myocardial infarction-associated transcript (miat) was first identified as an HCC specific SALncRNA. Knockdown of miat significantly promoted cellular senescence and inhibited HCC progression. Mechanistic study revealed that SAL-miat acted as a competitive endogenous RNA (ceRNA) that upregulated the expression of sirt1 by sponging miR-22-3p. Moreover, miat downregulation activated the tumor suppressor pathway (p53/p21 and p16/pRb) and stimulated senescent cancer cells to secrete senescence-associated secretory phenotype (SASP), which contributed to inhibition of tumor cell proliferation, and resulted in the suppression of HCC tumorigenesis. Together, our study provided mechanistic insights into a critical role of miat as a miRNA sponge in HCC cellular senescence, which might offer a potential therapeutic strategy for HCC treatment.

Long-term every-other-day administration of DMAMCL has little effect on aging and age-associated physiological decline in mice.

The activation of transcription factor NF-κB is currently identified as one of the driving forces to the aging process. Genetic impairment of NF-κB signaling pathway or pharmacological inhibition of NF-κB activity has been shown to extend healthspan and lifespan in animal models, and delay or reduce many age-related symptoms. However, the aging intervention strategies based on NF-κB inhibition by the suitable small molecular compound is currently still lacking. The water-soluble dimethylaminomicheliolide (DMAMCL), can inhibit NF-κB activity and is currently undergoing clinical trials. In this study, we showed that 15 months of DMAMCL administration started in 1-year old male mice was well-tolerated and safe, and improved or had little effect on some age-associated symptoms, such as neurobehavioral phenotypes, physical performance, cardiac function, hematological parameters, immune aging phenotypes, clinical chemistry parameters, and glucose homeostasis. At the molecular level, DMAMCL administration mitigated serum levels of several age-associated inflammatory cytokines, including IL-6, IL-1α, IL-1ß, TNF-α, IFN-γ, and CXCL2, and inhibited NF-κB activity in several aged tissues. Collectively, our results indicate that current strategy of DMAMCL administration may has little effect on aging process in mice, and provide basic clues to further exploit the possibility of DMAMCL-based aging intervention to promote healthy aging.

The deubiquitinase OTUD5 regulates Ku80 stability and non-homologous end joining.

The ability of cells to repair DNA double-strand breaks (DSBs) is important for maintaining genome stability and eliminating oncogenic DNA lesions. Two distinct and complementary pathways, non-homologous end joining (NHEJ) and homologous recombination (HR), are employed by mammalian cells to repair DNA DSBs. Each pathway is tightly controlled in response to increased DSBs. The Ku heterodimer has been shown to play a regulatory role in NHEJ repair. Ku80 ubiquitination contributes to the selection of a DSB repair pathway by causing the removal of Ku heterodimers from DSB sites. However, whether Ku80 deubiquitination also plays a role in regulating DSB repair is unknown. To address this question, we performed a comprehensive study of the deubiquitinase specific for Ku80, and our study showed that the deubiquitinase OTUD5 serves as an important regulator of NHEJ repair by increasing the stability of Ku80. Further studies revealed that OTUD5 depletion impaired NHEJ repair, and hence reduced overall DSB repair. Furthermore, OTUD5-depleted cells displayed excess end resection; as a result, HR repair was facilitated by OTUD5 depletion during the S/G2 phase. In summary, our study demonstrates that OTUD5 is a specific deubiquitinase for Ku80 and establishes OTUD5 as an important and positive regulator of NHEJ repair.

Paradoxical effects of cellular senescence-inhibited gene involved in hepatocellular carcinoma migration and proliferation by ERK pathway and mesenchymal-like markers.

BACKGROUND: Cellular senescence-inhibited gene (CSIG) strongly prolongs the progression of replicative senescence. However, roles and mechanisms of CSIG in tumor progression have not been studied widely. METHODS: Roles of CSIG in migration and proliferation of SMMC7721 and Huh7 cells were analyzed by transwell or cell viability assays, respectively. Tumorigenicity assays were used to study whether CSIG knockdown could affect SMMC7721 proliferation in vivo. Next, Western blotting and RT-PCR were preformed to evaluate the effects of CSIG on P-ERK cascade and epithelial mesenchymal transformation markers. Then, the location and expression of CSIG protein was detected by immunofluorescence and Western blotting, respectively. Finally, the Cancer Genome Atlas dataset was used to analyze CSIG mRNA levels in hepatocellular carcinoma (HCC) and adjacent non-tumor tissues. RESULTS: In this study, we found that CSIG overexpression promoted SMMC7721 cell migration, and CSIG knockdown suppressed tumorigenicity of SMMC7721 cells. In contrast to expectation, CSIG up-regulation could significantly inhibit Huh7 cell growth and migration. CSIG could promote P-ERK activation and levels of mesenchymal-like markers in SMMC7721 cells, whereas CSIG suppressed P-ERK activation and levels of mesenchymal-like markers in Huh7 cells. CSIG protein was located in nucleoli as well as nucleoplasm of SMMC7721 cells, whereas CSIG protein was mainly expressed in the nucleoli rather than nucleoplasm of Huh7 cells. Finally, due to individual differences, raised or down-regulated trends of CSIG in HCC as compared with adjacent non-tumor tissues are different among various patient populations. CONCLUSION: In summary, these results indicate that CSIG might play different roles in SMMC7721 and Huh7 cells through regulating P-ERK pathway and mesenchymal-like markers. The differential distribution of CSIG might be an important factor that causes its different functions in SMMC7721 and Huh7 cells. CSIG might play different roles in various patient populations.

p53 ß-hydroxybutyrylation attenuates p53 activity.

p53 is an essential tumor suppressor, whose activity is finely tuned by the posttranslational modifications. Previous research has reported that ß-hydroxybutyrate (BHB) induces ß-hydroxybutyrylation (Kbhb), which is a novel histone posttranslational modification. Here we report that p53 is modified by kbhb and that this modification occurs at lysines 120, 319, and 370 of p53. We demonstrate that the level of p53 kbhb is dramatically increased in cultured cells treated with BHB and in thymus tissues of fasted mice, and that CBP catalyze p53 kbhb. We show that p53 kbhb results in lower levels of p53 acetylation and reduced expression of the p53 downstream genes p21 and PUMA, as well as reduced cell growth arrest and apoptosis in cultured cells under p53-activating conditions. Similar results were observed in mouse thymus tissue under starvation conditions, which result in increased concentrations of serum BHB, and in response to genotoxic stress caused by γ-irradiation to activate p53. Our findings thus show that BHB-mediated p53 kbhb is a novel mechanism of p53 activity regulation, which may explain the link between ketone bodies and tumor, and which may provide promising therapeutic target for cancer treatment.

Mitochondrion-processed TERC regulates senescence without affecting telomerase activities.

Mitochondrial dysfunctions play major roles in ageing. How mitochondrial stresses invoke downstream responses and how specificity of the signaling is achieved, however, remains unclear. We have previously discovered that the RNA component of Telomerase TERC is imported into mitochondria, processed to a shorter form TERC-53, and then exported back to the cytosol. Cytosolic TERC-53 levels respond to mitochondrial functions, but have no direct effect on these functions, suggesting that cytosolic TERC-53 functions downstream of mitochondria as a signal of mitochondrial functions. Here, we show that cytosolic TERC-53 plays a regulatory role on cellular senescence and is involved in cognition decline in 10 months old mice, independent of its telomerase function. Manipulation of cytosolic TERC-53 levels affects cellular senescence and cognition decline in 10 months old mouse hippocampi without affecting telomerase activity, and most importantly, affects cellular senescence in terc-/- cells. These findings uncover a senescence-related regulatory pathway with a non-coding RNA as the signal in mammals.

S100A13 promotes senescence-associated secretory phenotype and cellular senescence via modulation of non-classical secretion of IL-1α.

Senescent cells display the senescence-associated secretory phenotype (SASP) which plays important roles in cancer, aging, etc. Cell surface-bound IL-1α is a crucial SASP factor and acts as an upstream regulator to induce NF-κB activity and subsequent SASP genes transcription. IL-1α exports to cell surface via S100A13 protein-dependent non-classical secretory pathway. However, the status of this secretory pathway during cellular senescence and its role in cellular senescence remain unknown. Here, we show that S100A13 is up-regulated in various types of cellular senescence. S100A13 overexpression increases cell surface-associated IL-1α level, NF-κB activity and subsequent multiple SASP genes induction, whereas S100A13 knockdown has an opposite role. We also exhibit that Cu2+ level is elevated during cellular senescence. Lowering Cu2+ level decreases cell surface-bound IL-1α level, NF-κB activity and SASP production. Moreover, S100A13 overexpression promotes oncogene Ras-induced cell senescence (Ras OIS), Doxorubicin-induced cancer cell senescence (TIS) and replicative senescence, while impairment of non-classical secretory pathway of IL-1α delays cellular senescence. In addition, intervention of S100A13 affects multiple SASP and cellular senescence mediators including p38, γ-H2AX, and mTORC1. Taken together, our findings unveil a critical role of the non-classical secretory pathway of IL-1α in cellular senescence and SASP regulation.

RNA-binding protein RPS3 contributes to hepatocarcinogenesis by post-transcriptionally up-regulating SIRT1.

Although several studies indicate that RNA-binding proteins (RBPs) contribute to key steps in a variety of physiological processes and cancer, the detailed biological functions and mechanisms remain to be determined. By performing bioinformatics analysis using well-established hepatocellular carcinoma (HCC) datasets, we identified a set of HCC progression-associated RBPs (HPARBPs) and found that the global expression of HPARBPs was significantly correlated with patient prognosis. Among the 42 HPARBPs, human ribosomal protein S3 (RPS3) was one of the most abundant genes whose role remains uncharacterized in HCC. Gain- and loss-of-function analyses demonstrated that RPS3 promoted HCC tumorigenesis both in vitro and in vivo. Mechanistically, we revealed that silent information regulator 1 (SIRT1) was a critical target of RPS3 and was essential for sustaining the RPS3-induced malignant phenotypes of HCC cells. RPS3 stabilized SIRT1 mRNA by binding to AUUUA motifs in the 3448-3530 region of the 3' untranslated region (UTR) of SIRT1 mRNA. In addition, we found that (5-formylfuran-2-yl) methyl 4-hydroxy-2-methylenebutanoate (FMHM) inhibited HCC progression by repressing the RPS3/SIRT1 pathway. Our study unveils a novel extra-ribosomal role of RPS3 in facilitating hepatocarcinogenesis via the post-transcriptional regulation of SIRT1 expression and proposes that the RPS3/SIRT1 pathway serves as a potential therapeutic target in HCC.

The Cellular Senescence-Inhibited Gene Is Essential for PPM1A Myristoylation To Modulate Transforming Growth Factor ß Signaling.

The cellular senescence-inhibited gene (CSIG) is implicated in important biological processes, including cellular senescence and apoptosis. Our work showed that CSIG is involved in the myristoylation of the serine/threonine protein phosphatase PPM1A. Previous research has shown that myristoylation is necessary for PPM1A to dephosphorylate Smad2 and Smad3. However, the control and the biological significance of the myristoylation remain poorly understood. In this study, we found that CSIG knockdown disturbs PPM1A myristoylation and reduces the dephosphorylation by PPM1A of its substrate Smad2. By regulating PPM1A myristoylation, CSIG is involved in modulating the signaling of transforming growth factor ß (TGF-ß). Further study of the mechanism indicated that CSIG facilitates the interaction between N-myristoyltransferase 1 (NMT1) and PPM1A. Taking the data together, we found that CSIG is a regulator of PPM1A myristoylation and TGF-ß signaling. By promoting the myristoylation of PPM1A, CSIG enhanced the phosphatase activity of PPM1A and further inhibited TGF-ß signaling. This work not only extends the biological significance of CSIG but also provides new ideas and a reference for the study of the regulatory mechanism of myristoylation.

Mitochondrial Trafficking and Processing of Telomerase RNA TERC.

Mitochondrial dysfunctions play major roles in many diseases. However, how mitochondrial stresses are relayed to downstream responses remains unclear. Here we show that the RNA component of mammalian telomerase TERC is imported into mitochondria, processed to a shorter form TERC-53, and then exported back to the cytosol. We found that the import is regulated by PNPASE, and the processing is controlled by mitochondrion-localized RNASET2. Cytosolic TERC-53 levels respond to changes in mitochondrial functions but have no direct effect on these functions. These findings uncover a mitochondrial RNA trafficking pathway and provide a potential mechanism for mitochondria to relay their functional states to other cellular compartments.