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Two RING-Finger Ubiquitin E3 Ligases Regulate the Degradation of SPX4, An Internal Phosphate Sensor, for Phosphate homeostasis and Signaling in Rice

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Molecular Plant 2019年第8期12卷 1060-1074页

作者： Wenyuan Ruan Meina Guo Xueqing Wang Zhenhui Guo Zhuang Xu Lei Xu Hongyu Zhao Haiji Sun Chengqi Yan Keke Yi Key Laboratory of Plant Nutrition and Fertilizer Ministry of AgricultureInstitute of Agricultural Resources and Regional PlanningChinese Academy of Agricultural SciencesBeijing 100081China College of Life Science Shandong Normal UniversityJinan 250014China Ningbo Academy of Agriculture Sciences 19 Dehou StreetNingbo City 315000China

SPX-domain-containing proteins (SPXs) play an important role in inorganic phosphate (Pi) sensing,signaling,and transport in eukaryotes.In plants,SPXs are known to integrate cellular Pi status and negatively regulate the activity of Pi central regulators,the PHOSPATE STARVATION RESPONSE proteins (PHRs).The stability of SPXs,such as SPX4,is reduced under Pi-deficient conditions.However,the mechanisms by which SPXs are degraded remain unclear.In this study,using a yeast-twhybrid screen we iden.tified two RING-finger ubiquitin E3 ligases regulating SPX4 degradation,designated SDEL1 and SDEL2,which were post-transcriptionally induced by Pi starvation.We found that both SDELs were located in the nucleus and cytoplasm,had ubiquitin E3 ligase activity,and directly ubiquitinated the K^213 and K^299 lysine residues in SPX4 to regulate its stability.Furthermore,we found that PHR2,a Pi central regulator in rice,could compete with SDELs by interacting with SPX4 under Pi-sufficient conditions,which protected SPX4 from ubiquitination and degradation.Consistent with the biochemical function of SDEL1 and SDEL2,overexpression of SDEL1 or SDEL2 resulted in Pi overaccumulation and induced Pi-starvation signaling even under Pi-sufficient conditions.Conversely,their loss-of-function mutants displayed decreased Pi accumulation and reduced Pi-starvation signaling.Collectively,our study revealed that SDEL1 and SDEL2 facilitate the degradation of SPX4 to modulate PHR2 activity and regulate Pi homeostasis and Pi signaling in response to external Pi availability in rice.

关键词： rice SPX4 PHR2 ubiquitination Pi signaling Pi homeostasis phosphate regulation network

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UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGCip in hepatocellular carcinoma

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Signal Transduction and Targeted Therapy 2021年第6期6卷 1856-1868页

作者： Junjie Xu Lin Ji Yeling Ruan Zhe Wan Zhongjie Lin Shunjie Xia Liye Tao Junhao Zheng Liuxin Cai Yifan Wang Xiao Liang Xiujun Cai Key Laboratory of Laparoscopic Technology of Zhejiang Province Department of General SurgerySir Run-Run Shaw HospitalZhejiang University School of MedicineHangzhouChina Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and EquipmentHangzhouChina Zhejiang University Cancer Center HangzhouChina Liangzhu Laboratory Zhejiang University Medical CenterHangzhouChina

The treatment for hepatocellular carcinoma(HCC)is promising in recent years,but still facing critical challenges.The first targeted therapy,sorafenib,prolonged the overall survival by months.However,resistance often occurs,largely limits its efficacy.Sorafenib was found to target the electron transport chain complexes,which results in the generation of reactive oxygen species(ROS).To maintain sorafenib resistance and further facilitate tumor progression,cancer cells develop strategies to overcome excessive ROS production and obtain resistance to oxidative stress-induced cell death.In the present study,we investigated the roles of ROS in sorafenib resistance,and found suppressed ROS levels and reductive redox states in sorafenib-resistant HCC cells.Mitochondria in sorafenib-resistant cells maintained greater functional and morphological integrity under the treatment of sorafenib.However,cellular oxygen consumption rate and mitochondria DNA content analyses revealed fewer numbers of mitochondria in sorafenib-resistant cells.Further investigation attributed this finding to decreased mitochondrial biogenesis,likely caused by the accelerated degradation of peroxisome proliferator-activated receptor y coactivator ip(PGC1P).Mechanistic dissection showed that upregulated UBQLN1 induced PGCip degradation in a ubiquitination-independent manner to attenuate mitochondrial biogenesis and ROS production in sorafenib-resistant cells under sorafenib treatment.Furthermore,clinical investigations further indicated that the patients with higher UBQLN1 levels experienced worse recurrence-free survival.In conclusion,we propose a novel mechanism involving mitochondrial biogenesis and ROS homeostasis in sorafenib resistance,which may offer new therapeutic targets and strategies for HCC patients.

关键词： homeostasis resistance overcome

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Targeted Ptpn11 deletion in mice reveals the essential role of SHP2 in osteoblast differentiation and skeletal homeostasis

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Bone Research 2021年第1期9卷 75-85页

作者： Lijun Wang Huiliang Yang Jiahui Huang Shaopeng Pei Liyun Wang Jian Q.Feng Dian Jing Hu Zhao Henry M.Kronenberg Douglas C.Moore Wentian Yang Department of Orthopedic Surgery Brown University Alpert Medical School and Rhode Island HospitalProvidenceRI 02903USA Department of Mechanical Engineering University of DelawareNewarkDE DE19716USA Department of Biomedical Sciences Texas A&M College of Dentistry3302 Gaston AveDallasTX 75246USA Department of Comprehensive Dentistry Texas A&M College of Dentistry3302 Gaston AveDallasTX 75246USA Endocrine Unit Massachusetts General Hospital and Harvard Medical SchoolBostonMA 02114USA

The maturation and function of osteoblasts(OBs)rely heavily on the reversible phosphorylation of signaling proteins.To date,most of the work in OBs has focused on phosphorylation by tyrosyl kinases,but little has been revealed about dephosphorylation by protein tyrosine phosphatases(PTPases).SHP2(encoded by PTPN11)is a ubiquitously expressed PTPase.PTPN11 mutations are associated with both bone and cartilage manifestations in patients with Noonan syndrome(NS)and metachondromatosis(MC),although the underlying mechanisms remain elusive.Here,we report that SHP2 deletion in bone gamma-carboxyglutamate protein-expressing(Bglap+)bone cells leads to massive osteopenia in both trabecular and cortical bones due to the failure of bone cell maturation and enhanced osteoclast activity,and its deletion in Bglap+chondrocytes results in the onset of enchondroma and osteochondroma in aged mice with increased tubular bone length.Mechanistically,SHP2 was found to be required for osteoblastic differentiation by promoting RUNX2/OSTERIX signaling and for the suppression of osteoclastogenesis by inhibiting STAT3-mediated RANKL production by osteoblasts and osteocytes.These findings are likely to explain the compromised skeletal system in NS and MC patients and to inform the development of novel therapeutics to combat skeletal disorders.

关键词： skeletal homeostasis SHP2

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Porphyromonas gingivalis disrupts vascular endothelial homeostasis in a TLR-NF-κB axis dependent manner

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International Journal of Oral Science 2020年第3期12卷 249-257页

作者： Mengru Xie Qingming Tang Shaoling Yu Jiwei Sun Feng Mei Jiajia Zhao Lili Chen Department of Stomatology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration WuhanChina

Cardiovascular disease is still the leading cause of mortality worldwide.Vascular endothelial dysfunction is viewed as the initial step of most cardiovascular diseases.Many studies have indicated that periodontal pathogens,especially Porphyromonas gingivalis,are closely correlated with vascular endothelial homeostasis,but the function of P.gingivalis and the underlying mechanisms are still elusive.To illuminate the effects and elucidate the mechanisms of P.gingivalis on endothelial structural integrity,we developed P.gingivalis infection models in vivo and in vitro.Endothelial cell proliferation,differentiation and apoptosis were detected.Here,we showed that P.gingivalis can impair endothelial integrity by inhibiting cell proliferation and inducing endothelial mesenchymal transformation and apoptosis of endothelial cells,which reduce the cell levels and cause the endothelium to lose its ability to repair itself.A mechanistic analysis showed that TLR antagonist or NF-κB signalling inhibitor can largely rescue the damaged integrity of the endothelium caused by P.gingivalis,suggesting that TLR-NF-κB signalling plays a vital role in vascular endothelial homeostasis destroyed by P.gingivalis.These results suggest a potential intervention method for the prevention and treatment of cardiovascular disease.

关键词： gingivalis homeostasis prevention

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Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice

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Signal Transduction and Targeted Therapy 2021年第1期6卷 131-143页

作者： Xuekun Fu Bo Zhou Qinnan Yan Chu Tao Lei Qin Xiaohao Wu Sixiong Lin Sheng Chen Yumei Lai Xuenong Zou Zengwu Shao Meiqing Wang Di Chen Wenfei Jin Youqiang Song Huiling Cao Ge Zhang Guozhi Xiao School of Medicine Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Researchand Shenzhen Key Laboratory of Cell MicroenvironmentSouthern University of Science and Technology1088 Xue Yuan Road518055 ShenzhenGuangdongChina Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases School of Chinese MedicineHong Kong Baptist University999077 Hong KongSARChina Department of Biology Southern University of Science and Technology518055 ShenzhenChina School of Biomedical Sciences University of Hong Kong21 Sassoon RoadHong KongChina Department of Spine Surgery Orthopedic Research InstituteThe First Affiliated Hospital of Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of Orthopedics and Traumatology510080 GuangzhouChina Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and Technology430022 WuhanChina Department of Orthopedic Surgery Rush University Medical CenterChicagoIL 60612USA State Key Laboratory of Military Stomatology National Clinical Research Center for Oral DiseasesShanxi International Joint Research Center for Oral DiseasesDepartment of Oral Anatomy and Physiology and TMDSchool of Stomatologythe Fourth Military Medical University145 Changle West RoadXi’anChina Research Center for Human Tissues and Organs Degeneration Shenzhen Institutes of Advanced TechnologyChinese Academy of Sciences518055 ShenzhenChina

In vertebrates,the type 1 parathyroid hormone receptor(PTH1R)is a critical regulator of skeletal development and homeostasis;however,how it is modulated is incompletely understood.Here we report that deleting Kindlin-2 in osteoblastic cells using the mouse 10-kb Dmp1-Cre largely neutralizes the intermittent PTH-stimulated increasing of bone volume fraction and bone mineral density by impairing both osteoblast and osteoclast formation in murine adult bone.Single-cell profiling reveals that Kindlin-2 loss increases the proportion of osteoblasts,but not mesenchymal stem cells,chondrocytes and fibroblasts,in non-hematopoietic bone marrow cells,with concomitant depletion of osteoblasts on the bone surfaces,especially those stimulated by PTH.Furthermore,haploinsufficiency of Kindlin-2 and Pth1r genes,but not that of either gene,in mice significantly decreases basal and,to a larger extent,PTH-stimulated bone mass,supporting the notion that both factors function in the same genetic pathway.Mechanistically,Kindlin-2 interacts with the C-terminal cytoplasmic domain of PTH1R via aa 474–475 and Gsα.Kindlin-2 loss suppresses PTH induction of cAMP production and CREB phosphorylation in cultured osteoblasts and in bone.Interestingly,PTH promotes Kindlin-2 expression in vitro and in vivo,thus creating a positive feedback regulatory loop.Finally,estrogen deficiency induced by ovariectomy drastically decreases expression of Kindlin-2 protein in osteocytes embedded in the bone matrix and Kindlin-2 loss essentially abolishes the PTH anabolic activity in bone in ovariectomized mice.Thus,we demonstrate that Kindlin-2 functions as an intrinsic component of the PTH1R signaling pathway in osteoblastic cells to regulate bone mass accrual and homeostasis.

关键词： homeostasis Kindlin skeletal

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Ribosome biogenesis gene DEF/UTP25 is essential for liver homeostasis and regeneration

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Science China(Life Sciences) 2020年第11期63卷 1651-1664页

作者： Weidong Huang Feng Chen Quanxin Ma Jiaojiao Xin Jiaqi Li Jun Chen Bin Zhou Minli Chen Jun Li Jinrong Peng MOE Key Laboratory of Molecular Animal Nutrition College of Animal SciencesZhejiang UniversityHangzhou 310058China Academy of Chinese Medicine/Institute of Comparative Medicine Zhejiang Chinese Medical UniversityHangzhou 310053China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310003China College of Life Sciences Zhejiang UniversityHangzhou 310058China The State Key Laboratory of Cell Biology CAS Center for Excellence on Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China

Hepatocytes are responsible for diverse metabolic activities in a liver. Proper ribosome biogenesis is essential to sustain the function of hepatocytes. There are approximately 200 factors involved in ribosome biogenesis;however, few studies have focused on the role of these factors in maintaining liver homeostasis. The digestive organ expansion factor(def) gene encodes a nucleolar protein Def that participates in ribosome biogenesis. In addition, Def forms a complex with cysteine protease Calpain3(Capn3) and recruits Capn3 to the nucleolus to cleave protein targets. However, the function of Def has not been characterized in the mammalian digestive organs. In this report, we show that conditional knockout of the mouse def gene in hepatocytes causes cell morphology abnormality and constant infiltration of inflammatory cells in the liver. As age increases, the def conditional knockout liver displays multiple tissue damage foci and biliary hyperplasia. Moreover, partial hepatectomy leads to sudden acute death to the def conditional knockout mice and this phenotype is rescued by intragastric injection of the anti-inflammation drug dexamethasone one day before hepatectomy. Our results demonstrate that Def is essential for maintaining the liver homeostasis and liver regeneration capacity in mammals.

关键词： homeostasis organs inflammation

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Mapping the immune microenvironment for mandibular alveolar bone homeostasis at single-cell resolution

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Bone Research 2021年第1期9卷 97-108页

作者： Weimin Lin Qiwen Li Danting Zhang Xiaohan Zhang Xingying Qi Qian Wang Yaqian Chen Caojie Liu Hanwen Li Shiwen Zhang Yuan Wang Bin Shao Li Zhang Quan Yuan State Key Laboratory of Oral Diseases&National Clinical Research Center for Oral Diseases West China Hospital of StomatologySichuan UniversityChengduChina Department of Oral Implantology West China Hospital of StomatologySichuan UniversityChengduChina Department of Respiratory and Critical Care Medicine Frontiers Science Center for Disease-related Molecular NetworkCenter of Precision MedicinePrecision Medicine Key Laboratory of Sichuan ProvinceWest China HospitalSichuan UniversityChengduChina

Alveolar bone is the thickened ridge of jaw bone that supports teeth.It is subject to constant occlusal force and pathogens invasion,and is therefore under active bone remodeling and immunomodulation.Alveolar bone holds a distinct niche from long bone considering their different developmental origin and postnatal remodeling pattern.However,a systematic explanation of alveolar bone at single-cell level is still lacking.Here,we construct a single-cell atlas of mouse mandibular alveolar bone through single-cell RNA sequencing(scRNA-seq).A more active immune microenvironment is identified in alveolar bone,with a higher proportion of mature immune cells than in long bone.Among all immune cell populations,the monocyte/macrophage subpopulation most actively interacts with mesenchymal stem cells(MSCs)subpopulation.Alveolar bone monocytes/macrophages express a higher level of Oncostatin M(Osm)compared to long bone,which promotes osteogenic differentiation and inhibits adipogenic differentiation of MSCs.In summary,our study reveals a unique immune microenvironment of alveolar bone,which may provide a more precise immune-modulatory target for therapeutic treatment of oral diseases.

关键词： alveolar mandibular homeostasis

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Inflammatory processes in the liver: divergent roles in homeostasis and pathology

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Cellular & Molecular Immunology 2021年第6期18卷 1375-1386页

作者： Ola Ahmed Mark W.Robinson Cliona O’Farrelly School of Medicine Trinity College DublinDublinIreland Department of Biology Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynoothIreland School of Biochemistry&Immunology Trinity College DublinDublin 2Ireland

The hepatic immune system is designed to tolerate diverse harmless foreign moieties to maintain homeostasis in the healthy liver.Constant priming and regulation ensure that appropriate immune activation occurs when challenged by pathogens and tissue damage.Failure to accurately discriminate,regulate,or effectively resolve inflammation offsets this balance,jeopardizing overall tissue health resulting from an either overly tolerant or an overactive inflammatory response.Compelling scientific and clinical evidence links dysregulated hepatic immune and inflammatory responses upon sterile injury to several pathological conditions in the liver,particularly nonalcoholic steatohepatitis and ischemia-reperfusion injury.Murine and human studies have described interactions between diverse immune repertoires and nonhematopoietic cell populations in both physiological and pathological activities in the liver,although the molecular mechanisms driving these associations are not clearly understood.Here,we review the dynamic roles of inflammatory mediators in responses to sterile injury in the context of homeostasis and disease,the clinical implications of dysregulated hepatic immune activity and therapeutic developments to regulate liver-specific immunity.

关键词： homeostasis immunology inflammation liver

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Energy metabolism homeostasis in cardiovascular diseases

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Journal of Geriatric Cardiology 2021年第12期18卷 1044-1057页

作者： Lu-Yun WANG Chen CHEN Division of Cardiology Tongji HospitalTongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic DisordersHuazhong University of Science and TechnologyWuhanChina

Cardiovascular disease(CVD)is the leading cause of morbidity and mortality in the general population.Energy metabolism disturbance is one of the early abnormalities in CVDs,such as coronary heart disease,diabetic cardiomyopathy,and heart failure.To explore the role of myocardial energy homeostasis disturbance in CVDs,it is important to understand myocardial metabolism in the normal heart and their function in the complex pathophysiology of CVDs.In this article,we summarized lipid metabolism/lipotoxicity and glucose metabolism/insulin resistance in the heart,focused on the metabolic regulation during neonatal and ageing heart,proposed potential metabolic mechanisms for cardiac regeneration and degeneration.We provided an overview of emerging molecular network among cardiac proliferation,regeneration,and metabolic disturbance.These novel targets promise a new era for the treatment of CVDs.

关键词： metabolism homeostasis degeneration

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Exosomes-the enigmatic regulators of bone homeostasis

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Bone Research 2018年第4期6卷 303-315页

作者： Minhao Gao Weiyang Gao J. M. Papadimitriou Changqing Zhang Junjie Gao Minghao Zheng Centre for Orthopaedic Research Faculty of Health and Medical SciencesThe University of Western AustraliaNedlandsWA 6009Australia Perron Institute for Neurological and Translational Science NedlandsWA 6009Australia Department of Orthopaedics The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhouChina Pathwest laboratory PerthWAAustralia Department of Orthopaedics Shanghai Sixth People’s HospitalShanghai Jiaotong UniversityShanghaiChina

Exosomes are a heterogeneous group of cell-derived membranous structures, which mediate crosstalk interaction between cells.Recent studies have revealed a close relationship between exosomes and bone homeostasis. It is suggested that bone cells can spontaneously secret exosomes containing proteins, lipids and nucleic acids, which then to regulate osteoclastogenesis and osteogenesis. However, the network of regulatory activities of exosomes in bone homeostasis as well as their therapeutic potential in bone injury remain largely unknown. This review will detail and discuss the characteristics of exosomes, the regulatory activities of exosomes in bone homeostasis as well as the clinical potential of exosomes in bone injury.

关键词： Exosomes homeostasis suggested

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