Crosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System

Kocatürk, Nur Mehpare; Gözüaçık, Devrim

doi:10.3389/fcell.2018.00128

Cited by 332 publications

(314 citation statements)

References 371 publications

(412 reference statements)

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“…Aggregation-prone polyubiquitinated proteins are sometimes resistant to proteasomal degradation and must be recognized and removed by additional proteostasis response pathways, including the autophagy pathway (Ciechanover & Kwon, 2015, Cortes & La Spada, 2015, Kirkin, McEwan et al, 2009, Lim & Yue, 2015, Ryno, Wiseman et al, 2013. It is unclear how these different pathways are coordinated or how some substrates are preferred by one pathway over another (Kocaturk & Gozuacik, 2018).…”

Section: Introductionmentioning

confidence: 99%

Biogenic Amine Neurotransmitters Promote Eicosanoid Production And Protein Homeostasis

Rongo

Joshi

Matlack

et al. 2020

Preprint

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Multicellular organisms use multiple pathways to restore protein homeostasis (proteostasis) in response to adverse physiological conditions, changing environment, and developmental aging.The nervous system can regulate proteostasis in different tissues, but it is unclear how it mobilizes proteostasis pathways to offset physiological decline. Here we show that C. elegans employs the humoral biogenic amine neurotransmitters dopamine, serotonin, and tyramine to regulate proteostasis and the activity of the Ubiquitin Proteasome System (UPS) in epithelial tissues. Mutants for biogenic amine synthesis show decreased poly-ubiquitination and turnover of a GFP-based UPS substrate. Using RNA-seq, we determined the expression profile of genes regulated by biogenic amine signaling. We find that biogenic amines promote the expression of a subset of cytochrome P450 monooxygenases involved in eicosanoid production from polyunsaturated fatty acids (PUFAs). Mutants for these P450s share the same UPS phenotype observed in biogenic amine mutants. The production of n-3 PUFAs is required for UPS substrate turnover, whereas mutants that accumulate n-3 PUFAs show accelerated turnover of this GFP-based substrate. Our results suggest that neurosecretory sensory neurons release biogenic amines to modulate the lipid signaling profile, which in turn activates stress response pathways to maintain proteostasis.

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Section: Introductionmentioning

confidence: 99%

Biogenic Amine Neurotransmitters Promote Eicosanoid Production And Protein Homeostasis

Rongo

Joshi

Matlack

et al. 2020

Preprint

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“…Furthermore, the insoluble aggregates of GMPPB mutants completely colocalized with LC3‐II (the membrane type of LC3). In eukaryotes, autophagy–lysosome and ubiquitin–proteasome system (UPS) are two major quality control and recycling mechanisms responsible for cellular homeostasis . The UPS is responsible for the degradation of short‐lived proteins and soluble un/mis‐folded proteins, whereas autophagy‐lysosome eliminates long‐lived proteins, insoluble protein aggregates and degenerated organelles and intracellular parasites .…”

Section: Discussionmentioning

confidence: 99%

Lysosomal degradation of GMPPB is associated with limb‐girdle muscular dystrophy type 2T

Tian

Zhou

Zhan

et al. 2019

Ann Clin Transl Neurol

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Objective GDP‐mannose pyrophosphorylase B (GMPPB) related phenotype spectrum ranges widely from congenital myasthenic syndrome (CMS), limb‐girdle muscular dystrophy type 2T (LGMD 2T) to severe congenital muscle‐eye‐brain syndrome. Our study investigates the clinicopathologic features of a patient with novel GMPPB mutations and explores the pathogenetic mechanism. Methods The patient was a 22‐year‐old woman with chronic proximal limb weakness for 9 years without cognitive deterioration. Weakness became worse after fatigue. Elevated serum creatine kinase and decrements on repetitive nerve stimulation test were recorded. MRI showed fatty infiltration in muscles of lower limbs and shoulder girdle on T1 sequence. Open muscle biopsy and genetic analysis were performed. Results Muscle biopsy showed myogenic changes. Two missense mutations in GMPPB gene (c.803T>C and c.1060G>A) were identified in the patient. Western blotting and immunostaining showed GMPPB and α‐dystroglycan deficiency in the patient's muscle. In vitro, mutant GMPPB forming cytoplasmic aggregates completely colocalized with microtubule‐associated protein 1 light chain 3‐II (LC3‐II), a classical marker of autophagosome. Degradation of GMPPB was accompanied by an upregulation of LC3‐II, which could be restored by lysosomal inhibitor leupeptin. Interpretation We identified two novel GMPPB mutations causing overlap phenotype between LGMD 2T and CMS. We provided the initial evidence that mutant GMPPB colocalizes with autophagosome at subcellular level. GMPPB mutants degraded by autophagy‐lysosome pathway is associated with LGMD 2T. This study shed the light into the enzyme replacement which could become one of the therapeutic targets in the future study.

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“…Building on previous efforts to isolate autophagic clearance from induction 40, 59, 69 , here we created a system with the pivotal capacity to assess native autophagic flux, thereby avoiding several basic confounds associated with overexpression of autophagy reporters 70, 71 . This is of particular relevance considering the intersection between autophagy and nutrient/energy sensing 42 , the role of microtubule associated transport in autophagosome maturation 48 , and the crosstalk between autophagy and the ubiquitin proteasome system 44 . Increasing protein dosage can also induce aberrant aggregation of misfolded proteins, and influence the likelihood of protein phase separation 70, 72 .…”

Section: Discussionmentioning

confidence: 99%

“…Burdening the cell with non-physiological concentrations of substrate might artificially prolong flux estimates, or conversely enhance flux via regulatory feedback mechanisms. Moreover, because autophagy regulation is intricately tied to amino acid availability 42, 43 and the ubiquitin proteasome system 44 , any perturbations to these pathways brought on by protein overexpression may further confound measurements of flux.…”

Section: Introductionmentioning

confidence: 99%

Uncovering active modulators of native macroautophagy through novel high-content screens

Safren

Tank

Santoro³

et al. 2019

Preprint

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12Autophagy is an evolutionarily conserved pathway mediating the breakdown of cellular 13 proteins and organelles. Emphasizing its pivotal nature, autophagy dysfunction 14 contributes to many diseases; nevertheless, development of effective autophagy 15 modulating drugs is hampered by fundamental deficiencies in available methods for 16 measuring autophagic activity, or flux. To overcome these limitations, we introduced the 17 photoconvertible protein Dendra2 into the MAP1LC3B locus of human cells via 18 CRISPR/Cas9 genome editing, enabling accurate and sensitive assessments of 19 autophagy in living cells by optical pulse labeling. High-content screening of 1,500 tool 20 compounds provided construct validity for the assay and uncovered many new 21 autophagy modulators. In an expanded screen of 24,000 diverse compounds, we 22 identified additional hits with profound effects on autophagy. Further, the autophagy 23 activator NVP-BEZ235 exhibited significant neuroprotective properties in a 24 neurodegenerative disease model. These studies confirm the utility of the Dendra2-LC3 25 assay, while simultaneously highlighting new autophagy-modulating compounds that 26 display promising therapeutic effects. 27 28 Introduction 29 Macroautophagy (hereafter referred to as autophagy) is an essential pathway for 30 protein homeostasis whereby cytoplasmic proteins and organelles are delivered to 31 lysosomes for degradation 1 . Through the coordinated action of a series of autophagy-32 related (ATG) proteins and cargo receptors including p62/SQSTM1, NBR1, and 33 optinuerin 2 , substrates are sequestered within double membrane vesicles called 34 autophagosomes. Autophagosomes mature as they traffic along microtubules and 35 eventually fuse with lysosomes to form autolysosomes, wherein hydrolases degrade 36 autophagic cargo. The protein LC3 (ATG8) is an obligate component of autophagosome 37 membranes and is itself degraded within autolysosomes. For these reasons, it often 38 2 serves as both a marker of autophagosomes and as a representative autophagy 39 substrate 3 . 40Underscoring the critical requirement of autophagy in cellular homeostasis, 41 deletion of core autophagy genes in mice results in embryonic lethality 4,5,6 . Accordingly, 42 dysfunctional autophagy is linked to a wide spectrum of human disease including 43 neurodegeneration, cancer, metabolic disorders, infectious and cardiovascular 44 diseases 7 . Often these conditions involve deficiencies in one or more steps of 45 autophagy, resulting in impaired clearance of potentially toxic cellular components, 46 and/or a failure to replenish amino acids required for anabolic processes. In these 47 instances, enhancing the rate of autophagic cargo clearance, commonly referred to as 48 flux, would be beneficial. Conversely, autophagy can promote tumor progression and 49 resistance to chemotherapy for some cancers 8,9,10,11 . Here, autophagy inhibition may 50 represent a more apt therapeutic strategy 7 . 51Autophagy is of particular importance in the central nervous system...

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Crosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System

Cited by 332 publications

References 371 publications

Biogenic Amine Neurotransmitters Promote Eicosanoid Production And Protein Homeostasis

Biogenic Amine Neurotransmitters Promote Eicosanoid Production And Protein Homeostasis

Lysosomal degradation of GMPPB is associated with limb‐girdle muscular dystrophy type 2T

Uncovering active modulators of native macroautophagy through novel high-content screens

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