Редактирование: NBR1

Next to BRCA1 gene 1 protein (Cell migration-inducing gene 19 protein) (Membrane component chromosome 17 surface marker 2) (Neighbor of BRCA1 gene 1 protein) (Protein 1A1-3B) [1A13B] [KIAA0049] [M17S2] [MIG19]

==Publications==

{{medline-entry
|title=Autophagy receptor [[OPTN]] (optineurin) regulates mesenchymal stem cell fate and bone-fat balance during aging by clearing [[FABP3]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33143524
|abstract=Senile osteoporosis (OP) is often concomitant with decreased autophagic activity. [[OPTN]] (optineurin), a macroautophagy/autophagy (hereinafter referred to as autophagy) receptor, is found to play a pivotal role in selective autophagy, coupling autophagy with bone metabolism. However, its role in osteogenesis is still mysterious. Herein, we identified [i]Optn[/i] as a critical molecule of cell fate decision for bone marrow mesenchymal stem cells (MSCs), whose expression decreased in aged mice. Aged mice revealed osteoporotic bone loss, elevated senescence of MSCs, decreased osteogenesis, and enhanced adipogenesis, as well as [i]optn [/i]   mice. Importantly, restoring [i]Optn[/i] by transplanting wild-type MSCs to [i]optn [/i]   mice or infecting [i]optn [/i]   mice with [i]Optn[/i]-containing lentivirus rescued bone loss. The introduction of a loss-of-function mutant of [i]Optn [/i] failed to reestablish a bone-fat balance. We further identified [[FABP3]] (fatty acid binding protein 3, muscle and heart) as a novel selective autophagy substrate of [[OPTN]]. [[FABP3]] promoted adipogenesis and inhibited osteogenesis of MSCs. Knockdown of [[FABP3]] alleviated bone loss in [i]optn [/i]   mice and aged mice. Our study revealed that reduced [[OPTN]] expression during aging might lead to OP due to a lack of [[FABP3]] degradation via selective autophagy. [[FABP3]] accumulation impaired osteogenesis of MSCs, leading to the occurrence of OP. Thus, reactivating [[OPTN]] or inhibiting [[FABP3]] would open a new avenue to treat senile OP.   ADIPOQ: adiponectin, C1Q and collagen domain containing; ALPL: alkaline phosphatase, liver/bone/kidney; BGLAP/OC/osteocalcin: bone gamma carboxyglutamate protein; BFR/BS: bone formation rate/bone surface; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A/p21: cyclin-dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CDKN2B/p15: cyclin dependent kinase inhibitor 2B; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; COL1A1: collagen, type I, alpha 1; Ct. BV/TV: cortical bone volume fraction; Ct. Th: cortical thickness; Es. Pm: endocortical perimeter; FABP4/Ap2: fatty acid binding protein 4, adipocyte; H2AX: H2A.X variant histone; HE: hematoxylin and eosin; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MAR: mineral apposition rate; MSCs: bone marrow mesenchymal stem cells; [[NBR1]]: [[NBR1]], autophagy cargo receptor; OP: osteoporosis; [[OPTN]]: optineurin; PDB: Paget disease of bone; PPARG: peroxisome proliferator activated receptor gamma; Ps. Pm: periosteal perimeter; qRT-PCR: quantitative real-time PCR; γH2AX: Phosphorylation of the Serine residue of H2AX; ROS: reactive oxygen species; RUNX2: runt related transcription factor 2; SA-[[GLB1]]: senescence-associated (SA)-[[GLB1]] (galactosidase, beta 1); SP7/Osx/Osterix: Sp7 transcription factor 7; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 (human T cell leukemia virus type I) binding protein 1; Tb. BV/TV: trabecular bone volume fraction; Tb. N: trabecular number; Tb. Sp: trabecular separation; Tb. Th: trabecular thickness; μCT: micro computed tomography.

|keywords=* Adipogenesis
* autophagy
* bone metabolism
* fabp3
* mesenchymal stem cell
* optineurin
* osteogenesis
* osteoporosis
* senescence
|full-text-url=https://sci-hub.do/10.1080/15548627.2020.1839286
}}
{{medline-entry
|title=New insights into At[[NBR1]] as a selective autophagy cargo receptor in Arabidopsis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33124509
|abstract=Selective autophagy, mediated by cargo receptors and recruiting specific targets to autophagosomes for degradation and recycling, plays an important role in quality control and cellular homeostasis in eukaryotes. The Arabidopsis At[[NBR1]] shares a similar domain organization with the mammalian autophagic receptors p62 and [[NBR1]]. We recently demonstrated that At[[NBR1]] functions as a selective autophagy receptor for the exocyst component AtExo70E2, a marker for the Exocyst-positive organelle (EXPO), which was achieved via a specific ATG8-At[[NBR1]]-AtExo70E2 interaction in Arabidopsis. Here we further showed that [i]nbr1[/i] CRISPR mutants exhibit an early senescence phenotype under short-day growth conditions, which can be restored by complementation with expression of [i]At[[NBR1]]pro::At[[NBR1]]-GFP[/i] in the mutant. Interestingly, in addition to the typical cytosolic and punctate patterns, YFP-At[[NBR1]] also exhibited a microtubule pattern particularly in the cortical layer. Treatments with the microtubule depolymerizer oryzalin but not the microfilament depolymerizer latrunculin B abolished the microtubule pattern and affected the vacuolar delivery of YFP-At[[NBR1]] upon autophagy induction. These results indicated that microtubules may be required for At[[NBR1]] to shuttle its cargos to the vacuole during plant autophagy. The present study thus sheds new light on the recognition and movement pattern of At[[NBR1]] in selective autophagy in Arabidopsis.

|keywords=* AtNBR1
* UBA domain
* early senescence
* microtubule
* selective autophagy
|full-text-url=https://sci-hub.do/10.1080/15592324.2020.1839226
}}
{{medline-entry
|title=[[SQSTM1]]/p62 and [[PPARGC1A]]/PGC-1alpha at the interface of autophagy and vascular senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31441382
|abstract=Defective macroautophagy/autophagy and mitochondrial dysfunction are known to stimulate senescence. The mitochondrial regulator [[PPARGC1A]] (peroxisome proliferator activated receptor gamma, coactivator 1 alpha) regulates mitochondrial biogenesis, reducing senescence of vascular smooth muscle cells (VSMCs); however, it is unknown whether autophagy mediates [[PPARGC1A]]-protective effects on senescence. Using [i]ppargc1a [/i] VSMCs, we identified the autophagy receptor [[SQSTM1]]/p62 (sequestosome 1) as a major regulator of autophagy and senescence of VSMCs. Abnormal autophagosomes were observed in VSMCs in aortas of [i]ppargc1a [/i] mice. [i]ppargc1a [/i] VSMCs in culture presented reductions in LC3-II levels; in autophagosome number; and in the expression of [[SQSTM1]] (protein and mRNA), [[LAMP2]] (lysosomal-associated membrane protein 2), [[CTSD]] (cathepsin D), and [[TFRC]] (transferrin receptor). Reduced [[SQSTM1]] protein expression was also observed in aortas of [i]ppargc1a [/i] mice and was upregulated by [[PPARGC1A]] overexpression, suggesting that [[SQSTM1]] is a direct target of [[PPARGC1A]]. Inhibition of autophagy by 3-MA (3 methyladenine), spautin-1 or [i]Atg5[/i] (autophagy related 5) siRNA stimulated senescence. Rapamycin rescued the effect of [i]Atg5[/i] siRNA in [i]Ppargc1a [/i] , but not in [i]ppargc1a [/i] VSMCs, suggesting that other targets of [[MTOR]] (mechanistic target of rapamycin kinase), in addition to autophagy, also contribute to senescence. [i]Sqstm1[/i] siRNA increased senescence basally and in response to [[AGT]] II (angiotensin II) and zinc overload, two known inducers of senescence. Furthermore, [i]Sqstm1 [/i]gene deficiency mimicked the phenotype of [i]Ppargc1a[/i] depletion by presenting reduced autophagy and increased senescence [i]in vitro[/i] and [i]in vivo[/i]. Thus, [[PPARGC1A]] upregulates autophagy reducing senescence by a [[SQSTM1]]-dependent mechanism. We propose [[SQSTM1]] as a novel target in therapeutic interventions reducing senescence. 3-MA: 3 methyladenine; ACTA2/SM-actin: actin, alpha 2, smooth muscle, aorta; ACTB/β-actin: actin beta; [[AGT]] II: angiotensin II; ATG5: autophagy related 5; BECN1: beclin 1; CAT: catalase; CDKN1A: cyclin-dependent kinase inhibitor 1A (P21); Chl: chloroquine; [[CTSD]]: cathepsin D; CYCS: cytochrome C, somatic; DHE: dihydroethidium; DPBS: Dulbecco's phosphate-buffered saline; EL: elastic lamina; EM: extracellular matrix; FDG: fluorescein-di-β-D-galactopyranoside; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; γH2AFX: phosphorylated H2A histone family, member X, H DCFDA: 2',7'-dichlorodihydrofluorescein diacetate; [[LAMP2]]: lysosomal-associated membrane protein 2; MASMs: mouse vascular smooth muscle cells; MEF: mouse embryonic fibroblast; [[NBR1]]: [[NBR1]], autophagy cargo receptor; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; [[MTOR]]: mechanistic target of rapamycin kinase; NFE2L2: nuclear factor, erythroid derived 2, like 2; NOX1: NADPH oxidase 1; OPTN: optineurin; PFA: paraformaldehyde; PFU: plaque-forming units; [[PPARGC1A]]/PGC-1α: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; Ptdln3K: phosphatidylinositol 3-kinase; RASMs: rat vascular smooth muscle cells; ROS: reactive oxygen species; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; SASP: senescence-associated secretory phenotype; SIRT1: sirtuin 1; Spautin 1: specific and potent autophagy inhibitor 1; [[SQSTM1]]/p62: sequestosome 1; SOD: superoxide dismutase; TEM: transmission electron microscopy; TFEB: transcription factor EB; [[TFRC]]: transferrin receptor; TRP53/p53: transformation related protein 53; TUBG1: tubulin gamma 1; VSMCs: vascular smooth muscle cells; WT: wild type.

|keywords=* Aging
* SQSTM1
* autophagy
* oxidative stress
* senescence
* vascular biology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469683
}}
{{medline-entry
|title=Nrf2 mediates the expression of [[BAG3]] and autophagy cargo adaptor proteins and tau clearance in an age-dependent manner.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29304346
|abstract=During aging, decreased efficiency of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation and autophagic processes in the brain may be a contributing factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Therefore, we analyzed the expression of Bcl-2-associated athanogene 3, a cochaperone that mediates autophagy, and the autophagy adaptors [[NBR1]], NDP52, and sequestosome 1/p62 in the brains of 4-, 8-, and 12-month-old wild-type and Nrf2 knockout (-/-) mice. We also analyzed the levels of total tau and phospho-tau species. There were minimal differences in the expression of autophagy-related genes or tau species in 4-month-old animals; however, by 12 months, all of these autophagy-associated genes were expressed at significantly lower levels in the Nrf2 (-/-) mice. The decreases in the autophagy-associated genes were accompanied by significantly elevated levels of phospho-tau species in the 12-month-old Nrf2 (-/-) brains. These findings indicate that Nrf2 regulation of autophagy-related genes likely plays a greater role in mediating the clearance of tau as an organism ages.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aging
* Alzheimer Disease
* Animals
* Apoptosis Regulatory Proteins
* Autophagy
* Autophagy-Related Proteins
* Brain
* Gene Expression
* Mice, Inbred C57BL
* Mice, Knockout
* NF-E2-Related Factor 2
* Neurodegenerative Diseases
* tau Proteins
|keywords=* Autophagy adaptors
* BAG3
* Nrf2
* Tau
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801049
}}
{{medline-entry
|title=Overweight in elderly people induces impaired autophagy in skeletal muscle.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28549989
|abstract=Sarcopenia is the gradual loss of skeletal muscle mass, strength and quality associated with aging. Changes in body composition, especially in skeletal muscle and fat mass are crucial steps in the development of chronic diseases. We studied the effect of overweight on skeletal muscle tissue in elderly people without reaching obesity to prevent this extreme situation. Overweight induces a progressive protein breakdown reflected as a progressive withdrawal of anabolism against the promoted catabolic state leading to muscle wasting. Protein turnover is regulated by a network of signaling pathways. Muscle damage derived from overweight displayed by oxidative and endoplasmic reticulum (ER) stress induces inflammation and insulin resistance and forces the muscle to increase requirements from autophagy mechanisms. Our findings showed that failure of autophagy in the elderly deprives it to deal with the cell damage caused by overweight. This insufficiently efficient autophagy leads to an accumulation of p62 and [[NBR1]], which are robust markers of protein aggregations. This impaired autophagy affects myogenesis activity. Depletion of myogenic regulatory factors (MRFs) without links to variations in myostatin levels in overweight patients suggest a possible reduction of satellite cells in muscle tissue, which contributes to declined muscle quality. This discovery has important implications that improve the understanding of aged-related atrophy caused by overweight and demonstrates how impaired autophagy is one of the main responsible mechanisms that aggravate muscle wasting. Therefore, autophagy could be an interesting target for therapeutic interventions in humans against muscle impairment diseases.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Autophagy
* Endoplasmic Reticulum Stress
* Female
* Gene Expression Regulation
* Humans
* Insulin Resistance
* Intracellular Signaling Peptides and Proteins
* Male
* Muscle, Skeletal
* Muscular Atrophy
* Myogenic Regulatory Factors
* Myostatin
* Overweight
* Oxidative Stress
* Proteins
* Sarcopenia
* Satellite Cells, Skeletal Muscle
* Sequestosome-1 Protein
* Signal Transduction
|keywords=* Aged-related atrophy
* Autophagy
* Elderly
* Myogenesis
* Overweight
|full-text-url=https://sci-hub.do/10.1016/j.freeradbiomed.2017.05.018
}}