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1.
Danyi Yang Man J. Livingston Zhiwen Liu Guie Dong Ming Zhang Jian-Kang Chen Zheng Dong 《Cellular and molecular life sciences : CMLS》2018,75(4):669-688
Diabetic kidney disease, a leading cause of end-stage renal disease, has become a serious public health problem worldwide and lacks effective therapies. Autophagy is a highly conserved lysosomal degradation pathway that removes protein aggregates and damaged organelles to maintain cellular homeostasis. As important stress-responsive machinery, autophagy is involved in the pathogenesis of various diseases. Emerging evidence has suggested that dysregulated autophagy may contribute to both glomerular and tubulointerstitial pathologies in kidneys under diabetic conditions. This review summarizes the recent findings regarding the role of autophagy in the pathogenesis of diabetic kidney disease and highlights the regulation of autophagy by the nutrient-sensing pathways and intracellular stress signaling in this disease. The advances in our understanding of autophagy in diabetic kidney disease will facilitate the discovery of a new therapeutic target for the prevention and treatment of this life-threatening diabetes complication. 相似文献
2.
Kaser A Niederreiter L Blumberg RS 《Cellular and molecular life sciences : CMLS》2011,68(22):3643-3649
The intestinal epithelium forms a highly active functional interface between the relatively sterile internal body surfaces
and the enormously complex and diverse microbiota that are contained within the lumen. Genetic models that allow for manipulation
of genes specifically in the intestinal epithelium have provided an avenue to understand the diverse set of pathways whereby
intestinal epithelial cells (IECs) direct the immune state of the mucosa associated with homeostasis versus either productive
or non-productive inflammation as occurs during enteropathogen invasion or inflammatory bowel disease (IBD), respectively.
These pathways include the unfolded protein response (UPR) induced by stress in the endoplasmic reticulum (ER), autophagy,
a self-cannibalistic pathway important for intracellular bacterial killing and proper Paneth cell function as well as the
interrelated functions of NOD2/NF-κB signaling which also regulate autophagy induction. Multiple genes controlling these IEC
pathways have been shown to be genetic risk factors for human IBD. This highlights the importance of these pathways not only
for proper IEC function but also suggesting that IECs may be one of the cellular originators of organ-specific and systemic
inflammation as in IBD. 相似文献
3.
Yanhan Dong Cuiyun Liu Yanfang Zhao Murugavel Ponnusamy Peifeng Li Kun Wang 《Cellular and molecular life sciences : CMLS》2018,75(2):291-300
Loss of functional cardiomyocytes is a major underlying mechanism for myocardial remodeling and heart diseases, due to the limited regenerative capacity of adult myocardium. Apoptosis, programmed necrosis, and autophagy contribute to loss of cardiac myocytes that control the balance of cardiac cell death and cell survival through multiple intricate signaling pathways. In recent years, non-coding RNAs (ncRNAs) have received much attention to uncover their roles in cell death of cardiovascular diseases, such as myocardial infarction, cardiac hypertrophy, and heart failure. In addition, based on the view that mitochondrial morphology is linked to three types of cell death, ncRNAs are able to regulate mitochondrial fission/fusion of cardiomyocytes by targeting genes involved in cell death pathways. This review focuses on recent progress regarding the complex relationship between apoptosis/necrosis/autophagy and ncRNAs in the context of myocardial cell death in response to stress. This review also provides insight into the treatment for heart diseases that will guide novel therapies in the future. 相似文献
4.
Toll-like receptor (TLR) signaling is linked to autophagy that facilitates elimination of intracellular pathogens. However,
it is largely unknown whether autophagy controls TLR signaling. Here, we report that poly(I:C) stimulation induces selective
autophagic degradation of the TLR adaptor molecule TRIF and the signaling molecule TRAF6, which is revealed by gene silencing
of the ubiquitin-editing enzyme A20. This type of autophagy induced formation of autophagosomes and could be suppressed by
an autophagy inhibitor and lysosomal inhibitors. However, this autophagy was not associated with canonical autophagic processes,
including involvement of Beclin-1 and conversion of LC3-I to LC3-II. Through screening of TRIF-interacting ‘autophagy receptors’
in human cells, we identified that NDP52 mediated the selective autophagic degradation of TRIF and TRAF6 but not TRAF3. NDP52
was polyubiquitinated by TRAF6 and was involved in aggregation of TRAF6, which may result in the selective degradation. Intriguingly,
only under the condition of A20 silencing, NDP52 could effectively suppress poly(I:C)-induced proinflammatory gene expression.
Thus, this study clarifies a selective autophagic mechanism mediated by NDP52 that works downstream of TRIF–TRAF6. Furthermore,
although A20 is known as a signaling fine-tuner to prevent excess TLR signaling, it paradoxically downregulates the fine-tuning
effect of NDP52 on TLR signaling. 相似文献
5.
Microautophagy: lesser-known self-eating 总被引:1,自引:1,他引:0
Microautophagy, the non-selective lysosomal degradative process, involves direct engulfment of cytoplasmic cargo at a boundary
membrane by autophagic tubes, which mediate both invagination and vesicle scission into the lumen. With its constitutive characteristics,
microautophagy of soluble substrates can be induced by nitrogen starvation or rapamycin via regulatory signaling complex pathways.
The maintenance of organellar size, membrane homeostasis, and cell survival under nitrogen restriction are the main functions
of microautophagy. In addition, microautophagy is coordinated with and complements macroautophagy, chaperone-mediated autophagy,
and other self-eating pathways. Three forms of selective microautophagy, including micropexophagy, piecemeal microautophagy
of the nucleus, and micromitophagy, share common ground with microautophagy to some degree. As the accumulation of experimental
data, the precise mechanisms that govern microautophagy are becoming more appreciated. Here, we review the microautophagic
molecular machinery, its physiological functions, and relevance to human diseases, especially in diseases involving multivesicular
bodies and multivesicular lysosomes. 相似文献
6.
Gengyang Shen Hui Ren Qi Shang Ting Qiu Xiang Yu Zhida Zhang Jinjing Huang Wenhua Zhao Yuzhuo Zhang De Liang Xiaobing Jiang 《Cellular and molecular life sciences : CMLS》2018,75(15):2683-2693
Autophagy takes part in regulating the eukaryotic cells function and the progression of numerous diseases, but its clinical utility has not been fully developed yet. Recently, mounting evidences highlight an important correlation between autophagy and bone homeostasis, mediated by osteoclasts, osteocytes, bone marrow mesenchymal stem cells, and osteoblasts, and autophagy plays a vital role in the pathogenesis of glucocorticoid-induced osteoporosis (GIOP). The combinations of autophagy activators/inhibitors with anti-GIOP first-line drugs or some new autophagy-based manipulators, such as regulation of B cell lymphoma 2 family proteins and caspase-dependent clearance of autophagy-related gene proteins, are likely to be the promising approaches for GIOP clinical treatments. In view of the important role of autophagy in the pathogenesis of GIOP, here we review the potential mechanisms about the impacts of autophagy in GIOP and its association with GIOP therapy. 相似文献
7.
Sami Reijonen Jyrki P. Kukkonen Alise Hyrskyluoto Jenny Kivinen Minna Kairisalo Nobuyuki Takei Dan Lindholm Laura Korhonen 《Cellular and molecular life sciences : CMLS》2010,67(11):1929-1941
Accumulation of abnormal proteins and endoplasmic reticulum stress accompany neurodegenerative diseases including Huntington’s
disease. We show that the expression of mutant huntingtin proteins with extended polyglutamine repeats differentially affected
endoplasmic reticulum signaling cascades linked to the inositol-requiring enzyme-1 (IRE1) pathway. Thus, the p38 and c-Jun
N-terminal kinase pathways were activated, while the levels of the nuclear factor-κB-p65 (NF-κB-p65) protein decreased. Downregulation
of NF-κB signaling was linked to decreased antioxidant levels, increased oxidative stress, and enhanced cell death. Concomitantly,
calpain was activated, and treatment with calpain inhibitors restored NF-κB-p65 levels and increased cell viability. The calpain
regulator, calpastatin, was low in cells expressing mutant huntingtin, and overexpression of calpastatin counteracted the
deleterious effects caused by N-terminal mutant huntingtin proteins. These results show that calpastatin and an altered NF-κB-p65
signaling are crucial factors involved in oxidative stress and cell death mediated by mutant huntingtin proteins. 相似文献
8.
Molecular mechanisms of nitrosative stress-mediated protein misfolding in neurodegenerative diseases
Nitrosative and oxidative stress, associated with the generation of excessive reactive oxygen or nitrogen species, are thought
to contribute to neurodegenerative disorders. Many such diseases are characterized by conformational changes in proteins that
result in their misfolding and aggregation. Accumulating evidence implies that at least two pathways affect protein folding:
the ubiquitin-proteasome system (UPS) and molecular chaperones. Normal protein degradation by the UPS can prevent accumulation
of aberrantly folded proteins. Molecular chaperones – such as protein-disulfide isomerase, glucose-regulated protein 78, and
heat shock proteins – can provide neuroprotection from aberrant proteins by facilitating proper folding and thus preventing
their aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Here,
we present evidence for the hypothesis that nitric oxide contributes to degenerative conditions by S-nitrosylating specific chaperones or UPS proteins that would otherwise prevent accumulation of misfolded proteins.
Received 5 December 2006; received after revision 7 February 2007; accepted 15 March 2007 相似文献
9.
Ellis JA 《Cellular and molecular life sciences : CMLS》2006,63(23):2702-2709
Emery-Dreifuss muscular dystrophy (EDMD) is a neuromuscular degenerative condition with an associated dilated cardiomyopathy
and cardiac conduction defect. It can be inherited in either an X-linked or autosomal manner by mutations in the nuclear proteins
emerin and lamin A/C, respectively. Traditionally muscular dystrophies were associated with defects in sarcolemma-associated
proteins and, therefore, a nuclear connection suggested the existence of novel signalling pathways associated with this group
of diseases. Subsequently, other mutations in the lamin A/C gene were attributed to a range of tissue-specific degenerative
conditions, collectively known as the ‘laminopathies’. Therefore, any proposed hypothesis underlying the molecular mechanism
of EDMD needs to include this anomaly. As we celebrate the 10th anniversary of the identification of emerin as a component
of the nuclear envelope, I discuss here the available evidence that currently implicates EDMD as arising from perturbations
in myogenic regulatory pathways, causing temporal delays in both cell cycle progression and muscle regeneration.
Received 25 May 2006; received after revision 22 June 2006; accepted 22 August 2006 相似文献
10.
Identification of rate-limiting steps or components of intracellular second messenger systems holds promise to effectively
interfere with these pathways under pathological conditions. The emerging literature on a recently identified family of signalling
regulator proteins, called tribbles gives interesting clues for how these proteins seem to link several ‘independent’ signal
processing systems together. Via their unique way of action, tribbles co-ordinate the activation and suppression of the various
interacting signalling pathways and therefore appear to be key in determining cell fate while responding to environmental
challenges. This review summarises our current understanding of tribbles function and also provides an evolutionary perspective
on the various tribbles genes.
Received 10 January 2006; received after revision 20 March 2006; accepted 5 April 2006 相似文献
11.
Gian Maria Fimia Mauro Piacentini 《Cellular and molecular life sciences : CMLS》2010,67(10):1581-1588
A growing number of publications show that apoptosis induction is often associated with increased autophagy indicating the
existence of an interplay between these two important cellular events. The simultaneous activation of both phenomena has been
detected not only in experimental settings but also in vivo under physiological and pathological conditions. Despite these
studies, the reciprocal influence of the two pathways in vivo has still not been completely understood. It is clear that autophagy
and apoptosis are strictly interconnected, as highlighted by the finding that the two pathways share key molecular regulators.
Many novel aspects of the crosstalk between
apoptosis and autophagy have recently emerged showing how complex is this
relationship and how critical is for the overall fate of the cell. In this mini-review we will focus on some key experiments
trying to decipher as to whether autophagy contributes to apoptosis modulation in vivo. 相似文献
12.
Hervé Hillaireau Patrick Couvreur 《Cellular and molecular life sciences : CMLS》2009,66(17):2873-2896
Nanocarriers offer unique possibilities to overcome cellular barriers in order to improve the delivery of various drugs and
drug candidates, including the promising therapeutic biomacromolecules (i.e., nucleic acids, proteins). There are various
mechanisms of nanocarrier cell internalization that are dramatically influenced by nanoparticles’ physicochemical properties.
Depending on the cellular uptake and intracellular trafficking, different pharmacological applications may be considered.
This review will discuss these opportunities, starting with the phagocytosis pathway, which, being increasingly well characterized
and understood, has allowed several successes in the treatment of certain cancers and infectious diseases. On the other hand,
the non-phagocytic pathways encompass various complicated mechanisms, such as clathrin-mediated endocytosis, caveolae-mediated
endocytosis and macropinocytosis, which are more challenging to control for pharmaceutical drug delivery applications. Nevertheless,
various strategies are being actively investigated in order to tailor nanocarriers able to deliver anticancer agents, nucleic
acids, proteins and peptides for therapeutic applications by these non-phagocytic routes. 相似文献
13.
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15.
Sumoylation regulates diverse biological processes 总被引:8,自引:0,他引:8
Zhao J 《Cellular and molecular life sciences : CMLS》2007,64(23):3017-3033
Ten years after its discovery, the small ubiquitin-like protein modifier (SUMO) has emerged as a key regulator of proteins.
While early studies indicated that sumoylation takes place mainly in the nucleus, an increasing number of non-nuclear substrates
have recently been identified, suggesting a wider stage for sumoylation in the cell. Unlike ubiquitylation, which primarily
targets a substrate for degradation, sumoylation regulates a substrate’s functions mainly by altering the intracellular localization,
protein-protein interactions or other types of post-translational modifications. These changes in turn affect gene expression,
genomic and chromosomal stability and integrity, and signal transduction. Sumoylation is counter-balanced by desumoylation,
and well-balanced sumoylation is essential for normal cellular behaviors. Loss of the balance has been associated with a number
of diseases. This paper reviews recent progress in the study of SUMO pathways, substrates, and cellular functions and highlights
important findings that have accelerated advances in this study field and link sumoylation to human diseases.
Received 19 March 2007; received after version 16 July 2007; accepted 1 August 2007 相似文献
16.
The parvins 总被引:5,自引:0,他引:5
The parvins are a family of proteins involved in linking integrins and associated proteins with intracellular pathways that
regulate actin cytoskeletal dynamics and cell survival. Both α-parvin (PARVA) and β-parvin (PARVB) localize to focal adhesions
and function in cell adhesion, spreading, motility and survival through interactions with partners, such as integrin-linked
kinase (ILK), paxillin, α-actinin and testicular kinase 1. A complex of PARVA with ILK and the LIM protein PINCH-1 is critical
for cell survival in a variety of cells, including certain cancer cells, kidney podocytes and cardiac myocytes. While PARVA
inhibits the activities of Rac1 and testicular kinase 1 and cell spreading, PARVB binds αPIX and α-actinin, and can promote
cell spreading. In contrast to PARVA, PARVB inhibits ILK activity and reverses some of its oncogenic effects in cancer cells.
This review focuses on the structure and function of the parvins and some possible roles in human diseases.
Received 5 August 2005; received after revision 5 September 2005; accepted 22 September 2005 相似文献
17.
BH3-only proteins in tumorigenesis and malignant melanoma 总被引:2,自引:0,他引:2
BH3-only proteins are a subset of the Bcl-2 family of apoptotic regulators. BH3-only proteins function as ‘damage sensors’
in the cell; they are activated in response to cellular stress or DNA damage, whereupon they initiate apoptosis. Apoptosis
is the primary mechanism by which the body rids itself of genetically defective cells and is critical for preventing the accumulation
of cells with tumorigenic potential. Therefore, dysregulation of BH3-only proteins may promote tumorigenesis. Furthermore,
functional apoptosis pathways are required for the success of most cancer treatments, including chemotherapy. Resistance to
chemotherapy, as seen with malignant melanoma, often reflects an inability of tumor cells to undergo apoptosis. By deciphering
the roles of BH3-only proteins in tumorigenesis, we may learn how to manipulate cell death pathways to overcome apoptotic
resistance. This review summarizes the current knowledge of BH3-only proteins and how they contribute to tumorigenesis, with
particular attention given to studies involving melanoma.
Received: 12 August 2006; received after revision: 2 October 2006; accepted 13 November 2006 相似文献
18.
Valerie Le Fourn Sujin Park Insook Jang Katarina Gaplovska-Kysela Bruno Guhl Yangsin Lee Jin Won Cho Christian Zuber Jürgen Roth 《Cellular and molecular life sciences : CMLS》2013,70(11):1985-2002
Multisubunit protein complexes are assembled in the endoplasmic reticulum (ER). Existing pools of single subunits and assembly intermediates ensure the efficient and rapid formation of complete complexes. While being kinetically beneficial, surplus components must be eliminated to prevent potentially harmful accumulation in the ER. Surplus single chains are cleared by the ubiquitin–proteasome system. However, the fate of not secreted assembly intermediates of multisubunit proteins remains elusive. Here we show by high-resolution double-label confocal immunofluorescence and immunogold electron microscopy that naturally occurring surplus fibrinogen Aα–γ assembly intermediates in HepG2 cells are dislocated together with EDEM1 from the ER to the cytoplasm in ER-derived vesicles not corresponding to COPII-coated vesicles originating from the transitional ER. This route corresponds to the novel ER exit path we have previously identified for EDEM1 (Zuber et al. Proc Natl Acad Sci USA 104:4407–4412, 2007). In the cytoplasm, detergent-insoluble aggregates of fibrinogen Aα–γ dimers develop that are targeted by the selective autophagy cargo receptors p62/SQSTM1 and NBR1. These aggregates are degraded by selective autophagy as directly demonstrated by high-resolution microscopy as well as biochemical analysis and inhibition of autophagy by siRNA and kinase inhibitors. Our findings demonstrate that different pathways exist in parallel for ER-to-cytoplasm dislocation and subsequent proteolytic degradation of large luminal protein complexes and of surplus luminal single-chain proteins. This implies that ER-associated protein degradation (ERAD) has a broader function in ER proteostasis and is not limited to the elimination of misfolded glycoproteins. 相似文献
19.
Axon degeneration is a pathophysiological process of axonal dying and breakdown, which is characterized by several morphological features including the accumulation of axoplasmic organelles, disassembly of microtubules, and fragmentation of the axonal cytoskeleton. Autophagy, a highly conserved lysosomal-degradation machinery responsible for the control of cellular protein quality, is widely believed to be essential for the maintenance of axonal homeostasis in neurons. In recent years, more and more evidence suggests that dysfunctional autophagy is associated with axonal degeneration in many neurodegenerative diseases. Here, we review the core machinery of autophagy in neuronal cells, and provide several major steps that interfere with autophagy flux in neurodegenerative conditions. Furthermore, this review highlights the potential role of neuronal autophagy in axon degeneration, and presents some possible molecular mechanisms by which dysfunctional autophagy leads to axon degeneration in pathological conditions. 相似文献
20.
Albert Lee Stephanie L. Rayner Serene S. L. Gwee Alana De Luca Hamideh Shahheydari Vinod Sundaramoorthy Audrey Ragagnin Marco Morsch Rowan Radford Jasmin Galper Sarah Freckleton Bingyang Shi Adam K. Walker Emily K. Don Nicholas J. Cole Shu Yang Kelly L. Williams Justin J. Yerbury Ian P. Blair Julie D. Atkin Mark P. Molloy Roger S. Chung 《Cellular and molecular life sciences : CMLS》2018,75(2):335-354
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase (SCFcyclin F) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin FS621G caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin FWT. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin FS621G-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin FS621G revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin FS621G disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. 相似文献