SUMOylation of Smad2 mediates TGF-ß-regulated endothelial-mesenchymal transition.

Endothelial-mesenchymal transition (EndoMT) is a complex biological process in which endothelial cells are transformed into mesenchymal cells, and dysregulated EndoMT causes a variety of pathological processes. Transforming growth factor beta (TGF-ß) signaling effectively induces the EndoMT process in endothelial cells, and Smad2 is the critical protein of the TGF-ß signaling pathway. However, whether small ubiquitin-like modifier modification (SUMOylation) is involved in EndoMT remains unclear. Here, we show that Smad2 is predominantly modified by SUMO1 at two major SUMOylation sites with PIAS2α as the primary E3 ligase, whereas SENP1 (sentrin/SUMO-specific protease 1) mediates the deSUMOylation of Smad2. In addition, we identified that SUMOylation significantly enhances the transcriptional activity and protein stability of Smad2, regulating the expression of downstream target genes. SUMOylation increases the phosphorylation of Smad2 and the formation of the Smad2-Smad4 complex, thus promoting the nuclear translocation of Smad2. Ultimately, the wildtype, but not SUMOylation site mutant Smad2 facilitated the EndoMT process. More importantly, TGF-ß enhances the nuclear translocation of Smad2 by enhancing its SUMOylation and promoting the EndoMT process. These results demonstrate that SUMOylation of Smad2 plays a critical role in the TGF-ß-mediated EndoMT process, providing a new theoretical basis for the treatment and potential drug targets of EndoMT-related clinical diseases.

Oncogenic role of the SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2+ diffuse large B-cell lymphomas.

Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, SOX9 was overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCLs) that harbor IGH-BCL2 translocations. SOX9 positivity in DLBCL correlated with an advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest, and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole-transcriptome analysis and chromatin immunoprecipitation-sequencing assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In models of DLBCL cell line xenografts, SOX9 knockdown resulted in a lower DHCR24 level, reduced cholesterol content, and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell lines with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrated that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCLs.

The SUMO-specific protease SENP2 plays an essential role in the regulation of Kv7.2 and Kv7.3 potassium channels.

Sentrin/small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2)-deficient mice develop spontaneous seizures in early life because of a marked reduction in M currents, which regulate neuronal membrane excitability. We have previously shown that hyper-SUMOylation of the Kv7.2 and Kv7.3 channels is critically involved in the regulation of the M currents conducted by these potassium voltage-gated channels. Here, we show that hyper-SUMOylation of the Kv7.2 and Kv7.3 proteins reduced binding to the lipid secondary messenger PIP2. CaM1 has been shown to be tethered to the Kv7 subunits via hydrophobic motifs in its C termini and implicated in the channel assembly. Mutation of the SUMOylation sites on Kv7.2 and Kv7.3 specifically resulted in decreased binding to CaM1 and enhanced CaM1-mediated assembly of Kv7.2 and Kv7.3, whereas hyper-SUMOylation of Kv7.2 and Kv7.3 inhibited channel assembly. SENP2-deficient mice exhibited increased acetylcholine levels in the brain and the heart tissue because of increases in the vagal tone induced by recurrent seizures. The SENP2-deficient mice develop seizures followed by a period of sinus pauses or atrioventricular conduction blocks. Chronic administration of the parasympathetic blocker atropine or unilateral vagotomy significantly prolonged the life of the SENP2-deficient mice. Furthermore, we showed that retigabine, an M-current opener, reduced the transcription of SUMO-activating enzyme SAE1 and inhibited SUMOylation of the Kv7.2 and Kv7.3 channels, and also prolonged the life of SENP2-deficient mice. Taken together, the previously demonstrated roles of PIP2, CaM1, and retigabine on the regulation of Kv7.2 and Kv7.3 channel function can be explained by their roles in regulating SUMOylation of this critical potassium channel.

The function of SUMOylation and its crucial roles in the development of neurological diseases.

Neurological diseases are relatively complex diseases of a large system; however, the detailed mechanism of their pathogenesis has not been completely elucidated, and effective treatment methods are still lacking for some of the diseases. The SUMO (small ubiquitin-like modifier) modification is a dynamic and reversible process that is catalyzed by SUMO-specific E1, E2, and E3 ligases and reversed by a family of SENPs (SUMO/Sentrin-specific proteases). SUMOylation covalently conjugates numerous cellular proteins, and affects their cellular localization and biological activity in numerous cellular processes. A wide range of neuronal proteins have been identified as SUMO substrates, and the disruption of SUMOylation results in defects in synaptic plasticity, neuronal excitability, and neuronal stress responses. SUMOylation disorders cause many neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and Huntington's disease. By modulating the ion channel subunit, SUMOylation imbalance is responsible for the development of various channelopathies. The regulation of protein SUMOylation in neurons may provide a new strategy for the development of targeted therapeutic drugs for neurodegenerative diseases and channelopathies.

The important roles of protein SUMOylation in the occurrence and development of leukemia and clinical implications.

Leukemia is a severe malignancy of the hematopoietic system, which is characterized by uncontrolled proliferation and dedifferentiation of immature hematopoietic precursor cells in the lymphatic system and bone marrow. Leukemia is caused by alterations of the genetic and epigenetic regulation of processes underlying hematologic malignancies, including SUMO modification (SUMOylation). Small ubiquitin-like modifier (SUMO) proteins covalently or noncovalently conjugate and modify a large number of target proteins via lysine residues. SUMOylation is a small ubiquitin-like modification that is catalyzed by the SUMO-specific activating enzyme E1, the binding enzyme E2, and the ligating enzyme E3. SUMO is covalently linked to substrate proteins to regulate the cellular localization of target proteins and the interaction of target proteins with other biological macromolecules. SUMOylation has emerged as a critical regulatory mechanism for subcellular localization, protein stability, protein-protein interactions, and biological function and thus regulates normal life activities. If the SUMOylation process of proteins is affected, it will cause a cellular reaction and ultimately lead to various diseases, including leukemia. There is growing evidence showing that a large number of proteins are SUMOylated and that SUMOylated proteins play an important role in the occurrence and development of various types of leukemia. Targeting the SUMOylation of proteins alone or in combination with current treatments might provide powerful targeted therapeutic strategies for the clinical treatment of leukemia.

Ambient ultraviolet B radiation induced valve behavioral acclimation of Pacific oyster which resulted from the different response strategies of smooth and striated adductor muscles.

Light not only conveys image-forming vision but also has an impact on various physiological functions. In particular, ultraviolet B (UVB) radiation has the closest relationship with living organisms. For Pacific oysters (Crassostrea gigas), alteration of valve behavior is one of the most important ways responding to ambient UVB. In the present study, the response of adult C. gigas to sunlight (especially UVB) was evaluated by monitoring valve activity and further elucidated at the physiological and metabolomic levels. After exposure, the valve activity of C. gigas demonstrated flexible acclimation to the ambient conditions. The potential adjustment of osmoregulation and oxidative stress might be related to ambient UVB radiation. Mycosporine-like amino acids might contribute to the protection of C. gigas against UVB, while precursors of ß-alanine and degradation products of 5-hydroxytryptamine might adjust the contraction of the adductor muscles. The different responses of the adductor muscles (smooth and striated) were manifested in signal transduction and metabolisms of energy and nucleotide. This study not only indicated the correlation between the valve behavioral changes in oysters and light radiation, especially UVB, but illustrated the acclimation strategies of oysters to ambient light (UVB) environment.

The Function of SUMOylation and Its Critical Roles in Cardiovascular Diseases and Potential Clinical Implications.

Cardiovascular disease (CVD) is a common disease caused by many factors, including atherosclerosis, congenital heart disease, heart failure, and ischemic cardiomyopathy. CVD has been regarded as one of the most common diseases and has a severe impact on the life quality of patients. The main features of CVD include high morbidity and mortality, which seriously threaten human health. SUMO proteins covalently conjugate lysine residues with a large number of substrate proteins, and SUMOylation regulates the function of target proteins and participates in cellular activities. Under certain pathological conditions, SUMOylation of proteins related to cardiovascular development and function are greatly changed. Numerous studies have suggested that SUMOylation of substrates plays critical roles in normal cardiovascular development and function. We reviewed the research progress of SUMOylation in cardiovascular development and function, and the regulation of protein SUMOylation may be applied as a potential therapeutic strategy for CVD treatment.

SUMO-specific protease 2 is essential for suppression of polycomb group protein-mediated gene silencing during embryonic development.

SUMO-specific protease 2 (SENP2) has a broad de-SUMOylation activity in vitro. However, the biological function of SENP2 is largely unknown. Here, we show that deletion of SENP2 gene in mouse causes defects in the embryonic heart and reduces the expression of Gata4 and Gata6, which are essential for cardiac development. SENP2 regulates transcription of Gata4 and Gata6 mainly through alteration of occupancy of Pc2/CBX4, a polycomb repressive complex 1 (PRC1) subunit, on its promoters. We demonstrate that Pc2/CBX4 is a target of SENP2 in vivo and that SUMOylation is essential for Pc2/CBX4-mediated PRC1 recruitment to methylated histone 3 at K27 (H3K27me3). In SENP2 null embryos, SUMOylated Pc2/CBX4 accumulates and Pc2/CBX4 occupancy on the promoters of PcG target genes is markedly increased, leading to repression of Gata4 and Gata6 transcription. Our results reveal a critical role for de-SUMOylation in the regulation of PcG target gene expression.

Induction of SENP1 in myocardium contributes to abnormities of mitochondria and cardiomyopathy.

Defect in mitochondrial biogenesis and cardiac energy metabolism is a critical contributing factor to cardiac hypertrophy and heart failure. Sentrin/SUMO specific protease 1 (SENP1) mediated regulation of PGC-1α transcriptional activity plays an essential role in mitochondrial biogenesis and mitochondrial function. However, whether SENP1 plays a role in cardiac hypertrophy and failure is unknown. We investigated whether alteration in SENP1 expression affects cardiomyopathy and the underlying mechanism. In our present study, we found that the expression of SENP1 was induced in mouse and human failing hearts associated with induced expression of mitochondrial genes. SENP1 expression in cardiomyocytes was induced by hypertrophic stimuli through calcium/calcineurin-NFAT3. SENP1 regulated mitochondrial gene expression by de-SUMOylation of MEF-2C, which enhanced MEF-2C-mediated PGC-1α transcription. Genetic induction of SENP1 led to mitochondrial dysregulation and cardiac dysfunction in vivo. Our data showed that pathogenesis of cardiomyopathy is attributed by SENP1 mediated regulation of mitochondrial abnormities. SENP1 up-regulation in diseased heart is mediated via calcineurin-NFAT/MEF2C-PGC-1α pathway.

An essential role of small ubiquitin-like modifier (SUMO)-specific Protease 2 in myostatin expression and myogenesis.

Sentrin/small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2) has broad de-SUMOylation activities in vitro, which is essential for embryonic heart development. Here, we show that myostatin, a key factor in skeletal muscle development, is markedly reduced in Senp2(-/-) mouse embryonic fibroblast cells and embryos. SENP2 regulates the transcription of myostatin mainly through de-SUMOylation of MEF2A. Silencing SENP2 can reduce myostatin expression and, therefore, promote myogenesis of skeletal muscle. These results reveal the important role of SENP2 in the regulation of myostatin expression and myogenesis.

Genetic dissection of ozone tolerance in rice (Oryza sativa L.) by a genome-wide association study.

Tropospheric ozone causes various negative effects on plants and affects the yield and quality of agricultural crops. Here, we report a genome-wide association study (GWAS) in rice (Oryza sativa L.) to determine candidate loci associated with ozone tolerance. A diversity panel consisting of 328 accessions representing all subgroups of O. sativa was exposed to ozone stress at 60 nl l(-1) for 7h every day throughout the growth season, or to control conditions. Averaged over all genotypes, ozone significantly affected biomass-related traits (plant height -1.0%, shoot dry weight -15.9%, tiller number -8.3%, grain weight -9.3%, total panicle weight -19.7%, single panicle weight -5.5%) and biochemical/physiological traits (symptom formation, SPAD value -4.4%, foliar lignin content +3.4%). A wide range of genotypic variance in response to ozone stress were observed in all phenotypes. Association mapping based on more than 30 000 single-nucleotide polymorphism (SNP) markers yielded 16 significant markers throughout the genome by applying a significance threshold of P<0.0001. Furthermore, by determining linkage disequilibrium blocks associated with significant SNPs, we gained a total of 195 candidate genes for these traits. The following sequence analysis revealed a number of novel polymorphisms in two candidate genes for the formation of visible leaf symptoms, a RING and an EREBP gene, both of which are involved in cell death and stress defence reactions. This study demonstrated substantial natural variation of responses to ozone in rice and the possibility of using GWAS in elucidating the genetic factors underlying ozone tolerance.

Simultaneous determination of trace migration of phthalate esters in honey and royal jelly by GC-MS.

A simple, rapid, and reliable liquid-liquid extraction coupled to GC-MS method was developed and validated for the quantification of 22 phthalate esters (PAEs) in honey and royal jelly. Instrument parameters for GC-MS were tested to obtain the satisfactory separation between 22 PAEs with high sensitivity. The extraction procedure was optimized in order to achieve the best recovery. The following criteria were used to validate the developed method: linearity, LOD, lower LOQ, precision, accuracy, matrix effect and carry-over. Correlation coefficients were >0.999 by applying the linear regression model based on the least-squares method with a weighting factor (1/x). The intra- and interday precision were within 12.7% in terms of RSD, and the accuracy was within -11.8% in terms of relative error. The mean extraction recoveries ranged between 80.1 and 110.9% for honey and royal jelly. No significant matrix effect and carry-over for PAEs were observed for the analysis of honey and royal jelly samples. A total of 20 real samples were analyzed for a mini-survey using the developed method. Seven PAEs in honey samples and five PAEs in royal jelly samples were found, indicating potential contamination with several PAEs.

SENP3-regulated Nodal signaling plays a potential role in cardiac left-right asymmetry development.

Congenital heart disease (CHD) is a type of major defect that occurs during embryonic development. Although significant advances have been made in the treatment of CHD, its etiology and molecular mechanism remain unclear. To identify the critical role of SUMOylation in cardiac development, we generated SENP3 knockout mice and showed that SENP3 knockout mice die on embryonic day 8.5 with an open neural tube and reversed left-right cardiac asymmetry. Moreover, SENP3 knockout promoted apoptosis and senescence of H9C2 cells. Further studies showed that Nodal, a critical gene that forms left-right asymmetry, is regulated by SENP3 and that SENP3 regulates cell apoptosis and senescence in a Nodal-dependent manner. Furthermore, Nodal was hyper-SUMOylated after SENP3 knockout, and SUMOylation of Nodal inhibited its ubiquitination and ubiquitin-proteasome degradation pathway. Nodal overexpression enhanced cell apoptosis and senescence; however, the mutation at the SUMOylation site of Nodal reversed its effect on the apoptosis and senescence of H9C2 cells. More importantly, the SENP3-Nodal axis regulates cell senescence by inducing cell autophagy. These results suggest that the SENP3-Nodal signaling axis regulates cardiac senescence-autophagy homeostasis, which in turn affects cardiac development and results in the occurrence of CHD.

SENP2-PLCß4 signaling regulates neurogenesis through the maintenance of calcium homeostasis.

Neurogenesis plays a critical role in brain physiology and behavioral performance, and defective neurogenesis leads to neurological and psychiatric disorders. Here, we show that PLCß4 expression is markedly reduced in SENP2-deficient cells and mice, resulting in decreased IP3 formation and altered intracellular calcium homeostasis. PLCß4 stability is regulated by the SUMO-dependent ubiquitin-mediated proteolytic pathway, which is catalyzed by PIAS2α and RNF4. SUMOylated PLCß4 is transported to the nucleus through Nup205- and RanBP2-dependent pathways and regulates nuclear signaling. Furthermore, dysregulated calcium homeostasis induced defects in neurogenesis and neuronal viability in SENP2-deficient mice. Finally, SENP2 and PLCß4 are stimulated by starvation and oxidative stress, which maintain calcium homeostasis regulated neurogenesis. Our findings provide mechanistic insight into the critical roles of SENP2 in the regulation of PLCß4 SUMOylation, and the involvement of SENP2-PLCß4 axis in calcium homeostasis regulated neurogenesis under stress.

Scallop IKK1 Responds to Bacterial and Virus-Related Pathogen Stimulation and Interacts With MyD88 Adaptor of Toll-Like Receptor Pathway Signaling.

IKK proteins are key signaling molecules in the innate immune system of animals, and act downstream of pattern recognition receptors. However, research on IKKs in invertebrates, especially marine mollusks, remains scarce. In this study, we cloned CfIKK1 gene from the Zhikong scallop (Chlamys farreri) and studied its function and the signaling it mediates. The open reading frame of CfIKK1 was 2190 bp and encoded 729 amino acids. Phylogenetic analysis showed that CfIKK1 belonged to the invertebrate IKKα/IKKß family. Quantitative real-time PCR analysis revealed the ubiquitous expression of CfIKK1 mRNA in all scallop tissues and challenge with lipopolysaccharide, peptidoglycan, or poly(I:C) significantly upregulated the expression of CfIKK1. Co-immunoprecipitation assays confirmed the interaction of CfIKK1 with scallop MyD88 (Myeloid differentiation actor 88, the key adaptor of the TLR signaling pathway) via its N-terminal kinase domain. Additionally, CfIKK1 protein could form homodimers and even oligomers, with N-terminal kinase domain and C-terminal scaffold dimerization domain playing key roles in this process. Finally, the results of RNAi experiments showed that when the scallop IKK1 gene was suppressed, the expression of IRF genes also decreased significantly. In conclusion, CfIKK1 could respond to PAMPs challenge and interact with MyD88 protein of scallop TLR signaling, with the formation of CfIKK1 dimers or oligomers. At the same time, the results of RNAi experiments revealed the close regulatory relationship between IKK1 and IRF genes of scallop. Therefore, as a key signal transduction molecule and immune activity regulator, CfIKK1 plays important roles in the innate immune system of scallops.

Scallop interferon regulatory factor 1 interacts with myeloid differentiation primary response protein 88 and is crucial for antiviral innate immunity.

The interferon regulatory factor (IRF) family comprises transcription factors that are crucial in immune defense, stress response, reproduction, and development. However, the function of IRFs in invertebrates is unclear. Here, the full-length cDNA of an IRF-encoding gene (CfIRF1) in the Zhikong scallop (Chlamys farreri) comprising 2007 bp with an open reading frame of 1053 bp that encoded 350 amino acids was characterized, and its immune function was studied. The CfIRF1 protein contained a typical IRF domain at its N-terminus. CfIRF1 was clustered with other proteins of the IRF1 subfamily, implying that they were closely related. CfIRF1 mRNA transcripts could be detected in all tested scallop tissues, with the highest expression observed in the gills and hepatopancreas. CfIRF1 expression was significantly induced by the polyinosinic-polycytidylic acid and acute viral necrosis virus challenge. CfIRF1 could directly interact with myeloid differentiation primary response protein 88 (MyD88), the key adaptor molecule of the toll-like receptor signaling pathway. CfIRF1 did not interact with scallop IKK1 (IKKα/ß family protein), IKK2, IKK3 (IKKε/TBK1 family protein), or with other IRF family proteins (IRF2 or IRF3). However, CfIRF1 interacted with itself to form a homodimer. CfIRF1 could specifically activate the interferon ß promoter of mammals and the promoter containing the interferon-stimulated response element (ISRE) in a dose-dependent manner. The truncated form of CfIRF1 had a significantly reduced ISRE activation ability, indicating that structural integrity was crucial for CfIRF1 to function as a transcription factor. Our findings provide insights into the functions of mollusk IRFs in innate immunity. The research results also provide valuable information that enriches the theory of comparative immunology and that can help prevent diseases in scallop farming.

SUMOylation Wrestles With the Occurrence and Development of Breast Cancer.

Breast cancer has the highest incidence among cancers and is the most frequent cause of death in women worldwide. The detailed mechanism of the pathogenesis of breast cancer has not been fully elucidated, and there remains a lack of effective treatment methods for the disease. SUMOylation covalently conjugates a large amount of cellular proteins, and affects their cellular localization and biological activity to participate in numerous cellular processes. SUMOylation is an important process and imbalance of SUMOylation results in the progression of human diseases. Increasing evidence shows that numerous SUMOylated proteins are involved in the occurrence and development of breast cancer. This review summarizes a series of studies on protein SUMOylation in breast cancer in recent years. The study of SUMOylated proteins provides a comprehensive understanding of the pathophysiology of breast cancer and provides evolving therapeutic strategies for the treatment of breast cancer.

Hyper-SUMOylation of ERG Is Essential for the Progression of Acute Myeloid Leukemia.

Leukemia is a malignant disease of hematopoietic tissue characterized by the differentiation arrest and malignant proliferation of immature hematopoietic precursor cells in bone marrow. ERG (ETS-related gene) is an important member of the E26 transformation-specific (ETS) transcription factor family that plays a crucial role in physiological and pathological processes. However, the role of ERG and its modification in leukemia remains underexplored. In the present study, we stably knocked down or overexpressed ERG in leukemia cells and observed that ERG significantly promotes the proliferation and inhibits the differentiation of AML (acute myeloid leukemia) cells. Further experiments showed that ERG was primarily modified by SUMO2, which was deconjugated by SENP2. PML promotes the SUMOylation of ERG, enhancing its stability. Arsenic trioxide decreased the expression level of ERG, further promoting cell differentiation. Furthermore, the mutation of SUMO sites in ERG inhibited its ability to promote the proliferation and inhibit the differentiation of leukemia cells. Our results demonstrated the crucial role of ERG SUMOylation in the development of AML, providing powerful targeted therapeutic strategies for the clinical treatment of AML.

Hyper-SUMOylation of SMN induced by SENP2 deficiency decreases its stability and leads to spinal muscular atrophy-like pathology.

Spinal muscular atrophy (SMA), a degenerative motor neuron disease and a leading cause of infant mortality, is caused by loss of functional survival motor neuron (SMN) protein due to SMN1 gene mutation. Here, using mouse and cell models for behavioral and histological studies, we found that SENP2 (SUMO/sentrin-specific protease 2)-deficient mice developed a notable SMA-like pathology phenotype with significantly decreased muscle fibers and motor neurons. At the molecular level, SENP2 deficiency in mice did not affect transcription but decreased SMN protein levels by promoting the SUMOylation of SMN. SMN was modified by SUMO2 with the E3 PIAS2α and deconjugated by SENP2. SUMOylation of SMN accelerated its degradation by the ubiquitin-proteasome degradation pathway with the ubiquitin E1 UBA1 (ubiquitin-like modifier activating enzyme 1) and E3 ITCH. SUMOylation of SMN increased its acetylation to inhibit the formation of Cajal bodies (CBs). These results showed that SENP2 deficiency induced hyper-SUMOylation of the SMN protein, which further affected the stability and functions of the SMN protein, eventually leading to the SMA-like phenotype. Thus, we uncovered the important roles for hyper-SUMOylation of SMN induced by SENP2 deficiency in motor neurons and provided a novel targeted therapeutic strategy for SMA. KEY MESSAGES: SENP2 deficiency enhanced the hyper-SUMOylation of SMN and promoted the degradation of SMN by the ubiquitin-proteasome pathway. SUMOylation increased the acetylation of SMN to inhibit CB formation. SENP2 deficiency caused hyper-SUMOylation of SMN protein, which further affected the stability and functions of SMN protein and eventually led to the occurrence of SMA-like pathology.

Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development.

Metabolic programming and mitochondrial dynamics along with T cell differentiation affect T cell fate and memory development; however, how to control metabolic reprogramming and mitochondrial dynamics in T cell memory development is unclear. Here, we provide evidence that the SUMO protease SENP1 promotes T cell memory development via Sirt3 deSUMOylation. SENP1-Sirt3 signalling augments the deacetylase activity of Sirt3, promoting both OXPHOS and mitochondrial fusion. Mechanistically, SENP1 activates Sirt3 deacetylase activity in T cell mitochondria, leading to reduction of the acetylation of mitochondrial metalloprotease YME1L1. Consequently, deacetylation of YME1L1 suppresses its activity on OPA1 cleavage to facilitate mitochondrial fusion, which results in T cell survival and promotes T cell memory development. We also show that the glycolytic intermediate fructose-1,6-bisphosphate (FBP) as a negative regulator suppresses AMPK-mediated activation of the SENP1-Sirt3 axis and reduces memory development. Moreover, glucose limitation reduces FBP production and activates AMPK during T cell memory development. These data show that glucose limitation activates AMPK and the subsequent SENP1-Sirt3 signalling for T cell memory development.