Lactate-Dependent Chaperone-Mediated Autophagy Induces Oscillatory Hif-1α Activity Promoting Proliferation of Hypoxic Cells

2019 ◽  
Author(s):  
Kshitiz Kz ◽  
Junaid Afzal ◽  
Archer Hamidzadeh ◽  
Hao Chang ◽  
Maimon E. Hubbi ◽  
...  
Keyword(s):  
Chaperone Mediated Autophagy

scholarly journals POS0375 CHAPERONE-MEDIATED AUTOPHAGY IS A HALLMARK OF JOINT DISEASE IN OSTEOARTHRITIC PATIENTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 418.1-418
Author(s):  
I. Lorenzo ◽  
U. Nogueira-Recalde ◽  
N. Oreiro ◽  
J. A. Pinto Tasende ◽  
M. Lotz ◽  
...  
Keyword(s):  
Lateral Meniscus ◽  
Joint Damage ◽  
Joint Disease ◽  
Expression Array ◽  
Knee Oa ◽  
Human Knee Joint ◽  
Gene And Protein Expression ◽  
Functional Consequences ◽  
Chaperone Mediated Autophagy ◽  
Grade Iii

Background:In Osteoarthritis (OA), defects in macroautophagy (autophagy) are evident and precede joint damage. Indeed, pharmacological activation of autophagy protects against joint damage.Objectives:Therefore, identifying hallmarks associated with specific autophagy subtypes could shed light to fundamental mechanisms of joint disease.Methods:A comparative analysis of 35 autophagy genes was performed from blood from the Prospective OA Cohort of A Coruña (PROCOAC). Non-OA subjects (Age:61,44±1,16 years; BMI:25,25±0,52; Females, n=18) and Knee OA subjects (Age:65,50±1,05 years; BMI:29,55±0,67; Females, n=18, OA grade III-IV) were profiled using an autophagy gene expression array by SYBR green qPCR. Confirmatory studies were performed in blood from Non-OA subjects (Age:60,13±1,12 years; BMI:24,85±0,59; Females; n=30) and Knee-OA subjects (Age:68,4±1,11 years; BMI:29,65±0,55; Females; n=30, OA grade III-IV) by Taqman qPCR. The candidate gene was evaluated in human knee joint tissues (cartilage, meniscus, ligaments, synovium) with different KL grades (Age: KL0=28,3±4,50; KL2=77±6,08; KL4=62,3±3,05, n=3) and in both spontaneous aging (2, 6, 12, 18, and 30 months old, n=3) and surgically-induced OA (10 weeks after surgery, n=4) in mice by IHC. The functional consequences were studied in T/C28a2 and primary human OA chondrocytes. Autophagy, FOXO, Chaperone-mediated autophagy (CMA), inflammation, and cellular senescence were analyzing by gene and protein expression. Moreover, oxidative stress and cell death were evaluated by FACS. The contribution of CMA to chondrocyte homeostasis was evaluated by studying the capacity of CMA to restore proteostasis upon autophagy deficiency by siATG5.Results:15 autophagy-related genes were significantly downregulated in blood from knee OA patients compared to non-OA patients. No significant upregulation was found for any studied gene, although a trend towards upregulation was found in genes involved in the mTOR pathway. Four key autophagy-related genes, including ATG16L2, ATG12, ATG4B and MAP1LC3B were found downregulated in knee OA patients. Interestingly, HSP90AA1 and HSPA8, CMA markers involved in stress response and protein folding, were downregulated. Confirmatory studies showed a significant downregulation of MAP1LC3B and HSP90AA1 in blood from knee OA patients. Remarkably, HSP90A was found reduced in femoral cartilage (medial and lateral), meniscus and ACL. Moreover, this reduction was higher in medial cartilage compared to lateral cartilage and meniscus, while in synovial membrane, HSP90A expression was found increased. This expression signature was dependent on OA grade severity. In addition, we observed a decrease of HSP90A with aging and OA in mice. The functional consequences of HSP90AA1 gene silencing are related to an increase in NFκB, MMP13, and p16 expression. Interestingly, LAMP2A, a key CMA mediator, HSPA8, MAP1LC3B and FoxO1 expression were upregulated in chondrocytes with HSP90AA1 deficiency, which might indicate an early response to maintain homeostasis. On the other hand, LAMP2A protein is decreased upon HSP90AA1 deficiency, while LC3II and p62 were increased, indicating a failure in the autophagy flux that leads to impaired lysosomal degradation.Moreover, p21, p16 and prbS6 were increased upon HSP90AA1 deficiency, besides increasing mitochondrial ROS production and apoptosis. ATG5 silencing blocks autophagy by reducing LC3II and increasing prbs6, p62, p16 and p21. Interestingly, LAMP2A and HSP90A were found increased, indicating a possible compensative activation of CMA in response to autophagy defects. These results support that HSP90A has an important role in chondrocyte homeostasis by participating in the cross-talk between CMA and autophagy.Conclusion:Taking together, we identified HSP90A, a CMA regulator, as critical in chondrocyte homeostasis. These disease mechanisms are relevant in OA and constitute hallmarks potentially useful to prevent OA progression.References:[1]Caramés B, et al. Arthritis Rheum. 2010, 2015;[2]Caramés B, et al. Ann Rheum Dis. 2012.Disclosure of Interests:None declared

Dysfunction of chaperone-mediated autophagy in human diseases

2021 ◽  
Author(s):  
Zhaozhong Liao ◽  
Bin Wang ◽  
Wenjing Liu ◽  
Qian Xu ◽  
Lin Hou ◽  
...  
Keyword(s):  
Human Diseases ◽  
Chaperone Mediated Autophagy

scholarly journals Humanin is an endogenous activator of chaperone-mediated autophagy

2017 ◽  
Vol 217 (2) ◽  
pp. 635-647 ◽  
Author(s):  
Zhenwei Gong ◽  
Inmaculada Tasset ◽  
Antonio Diaz ◽  
Jaime Anguiano ◽  
Emir Tas ◽  
...  
Keyword(s):  
Quality Control ◽  
Cell Death ◽  
Heat Shock Protein 90 ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Selective Degradation ◽  
Cytosolic Side ◽  
Chaperone Mediated Autophagy

Chaperone-mediated autophagy (CMA) serves as quality control during stress conditions through selective degradation of cytosolic proteins in lysosomes. Humanin (HN) is a mitochondria-associated peptide that offers cytoprotective, cardioprotective, and neuroprotective effects in vivo and in vitro. In this study, we demonstrate that HN directly activates CMA by increasing substrate binding and translocation into lysosomes. The potent HN analogue HNG protects from stressor-induced cell death in fibroblasts, cardiomyoblasts, neuronal cells, and primary cardiomyocytes. The protective effects are lost in CMA-deficient cells, suggesting that they are mediated through the activation of CMA. We identified that a fraction of endogenous HN is present at the cytosolic side of the lysosomal membrane, where it interacts with heat shock protein 90 (HSP90) and stabilizes binding of this chaperone to CMA substrates as they bind to the membrane. Inhibition of HSP90 blocks the effect of HNG on substrate translocation and abolishes the cytoprotective effects. Our study provides a novel mechanism by which HN exerts its cardioprotective and neuroprotective effects.

scholarly journals Ubiquilin functions in autophagy and is degraded by chaperone-mediated autophagy

2010 ◽  
Vol 19 (16) ◽  
pp. 3219-3232 ◽  
Author(s):  
C. Rothenberg ◽  
D. Srinivasan ◽  
L. Mah ◽  
S. Kaushik ◽  
C. M. Peterhoff ◽  
...  
Keyword(s):  
Chaperone Mediated Autophagy

scholarly journals Impairment of chaperone‐mediated autophagy leads to selective lysosomal degradation defects in the lysosomal storage disease cystinosis

2015 ◽  
Vol 7 (2) ◽  
pp. 158-174 ◽  
Author(s):  
Gennaro Napolitano ◽  
Jennifer L Johnson ◽  
Jing He ◽  
Celine J Rocca ◽  
Jlenia Monfregola ◽  
...  
Keyword(s):  
Lysosomal Storage Disease ◽  
Storage Disease ◽  
Lysosomal Storage ◽  
Lysosomal Degradation ◽  
Chaperone Mediated Autophagy

Molecular mechanisms of mammalian autophagy

2021 ◽  
Vol 478 (18) ◽  
pp. 3395-3421
Author(s):  
Charles B. Trelford ◽  
Gianni M. Di Guglielmo
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Molecular Pathways ◽  
Zymogen Granules ◽  
Ubiquitin Proteasome Pathway ◽  
Lysine Residues ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Functional Modulation ◽  
Chaperone Mediated Autophagy

The ubiquitin-proteasome pathway (UPP) and autophagy play integral roles in cellular homeostasis. As part of their normal life cycle, most proteins undergo ubiquitination for some form of redistribution, localization and/or functional modulation. However, ubiquitination is also important to the UPP and several autophagic processes. The UPP is initiated after specific lysine residues of short-lived, damaged or misfolded proteins are conjugated to ubiquitin, which targets these proteins to proteasomes. Autophagy is the endosomal/lysosomal-dependent degradation of organelles, invading microbes, zymogen granules and macromolecules such as protein, carbohydrates and lipids. Autophagy can be broadly separated into three distinct subtypes termed microautophagy, chaperone-mediated autophagy and macroautophagy. Although autophagy was once thought of as non-selective bulk degradation, advancements in the field have led to the discovery of several selective forms of autophagy. Here, we focus on the mechanisms of primary and selective mammalian autophagy pathways and highlight the current knowledge gaps in these molecular pathways.

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