scholarly journals ESCRT machinery mediates selective microautophagy of endoplasmic reticulum

2019 ◽  
Author(s):  
Jasmin A. Schäfer ◽  
Julia P. Schessner ◽  
Peter W. Bircham ◽  
Takuma Tsuji ◽  
Charlotta Funaya ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Lysosomal Membrane ◽  
Misfolded Proteins ◽  
Selective Autophagy ◽  
Escrt Machinery ◽  
Parallel Pathways ◽  
Mechanistic Understanding ◽  
Er Homeostasis ◽  
Er Whorls

ABSTRACTER-phagy, the selective autophagy of endoplasmic reticulum (ER), safeguards organelle homeostasis by eliminating misfolded proteins and regulating ER size. ER-phagy can occur by macroautophagic and microautophagic mechanisms. While dedicated machinery for macro-ER-phagy has been discovered, the molecules and mechanisms mediating micro-ER-phagy remain unknown. Here, we first show that micro-ER-phagy in yeast involves the conversion of stacked cisternal ER into multilamellar ER whorls during microautophagic uptake into lysosomes. Second, we identify the conserved Nem1-Spo7 phosphatase complex and ESCRT proteins as key components for micro-ER-phagy. Third, we demonstrate that macro- and micro-ER-phagy are parallel pathways with distinct molecular requirements. Finally, we provide evidence that ESCRT proteins directly function in scission of the lysosomal membrane to complete the microautophagic uptake of ER. These findings establish a framework for a mechanistic understanding of micro-ER-phagy and, thus, a comprehensive appreciation of the role of autophagy in ER homeostasis.

scholarly journals Autophagy in Neurons

2019 ◽  
Vol 35 (1) ◽  
pp. 477-500 ◽  
Author(s):  
Andrea K.H. Stavoe ◽  
Erika L.F. Holzbaur
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Biology ◽  
Neuronal Development ◽  
Selective Autophagy ◽  
The Core ◽  
Differentiated Cells ◽  
Neuronal Homeostasis ◽  
Core Components ◽  
Cellular Organelles

Autophagy is the major cellular pathway to degrade dysfunctional organelles and protein aggregates. Autophagy is particularly important in neurons, which are terminally differentiated cells that must last the lifetime of the organism. There are both constitutive and stress-induced pathways for autophagy in neurons, which catalyze the turnover of aged or damaged mitochondria, endoplasmic reticulum, other cellular organelles, and aggregated proteins. These pathways are required in neurodevelopment as well as in the maintenance of neuronal homeostasis. Here we review the core components of the pathway for autophagosome biogenesis, as well as the cell biology of bulk and selective autophagy in neurons. Finally, we discuss the role of autophagy in neuronal development, homeostasis, and aging and the links between deficits in autophagy and neurodegeneration.

Ubr1-induced selective endo-phagy/autophagy protects against the endosomal and Ca2+-induced proteostasis disease stress

2021 ◽  
Author(s):  
Ben B Wang ◽  
Haijin Xu ◽  
Sandra Isenmann ◽  
Cheng Huang ◽  
Xabier Elorza-Vidal ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Brain Disorders ◽  
Lysosomal Degradation ◽  
Defence Mechanisms ◽  
Selective Autophagy ◽  
Escrt Machinery ◽  
Endosomal Compartment ◽  
Regulatory Cluster

The defence mechanisms against endo-lysosomal homeostasis stress remain incompletely understood. Here, we identify Ubr1 as a protein quality control (QC) ubiquitin ligase that counteracts proteostasis stress by enhancing cargo selective autophagy for lysosomal degradation. Astrocyte regulatory cluster membrane protein MLC1 mutations increased intracellular Ca2+ and caused endosomal compartment stress by fusion and enlargement. Endosomal protein QC pathway using ubiquitin QC ligases CHIP and Ubr1 with ESCRT-machinery was able to target only a fraction of MLC1-mutants for lysosomal degradation. As a consequence of the endosomal stress, we found an alternative QC route dependent on Ubr1, SQSTM1/p62 and arginylation to bypass MLC1-mutants to endosomal autophagy (endo-phagy). Significantly, this unfolded a general biological endo-lysosomal QC pathway for arginylated Ubr1-SQSTM1/p62 autophagy targets during Ca2+-assault. Conversely, the loss of Ubr1 with the absence of arginylation elicited endosomal compartment stress. These findings underscore the critical housekeeping role of Ubr1-dependent endo-phagy/autophagy in constitutive and provoked endo-lysosomal proteostasis stress, and link Ubr1 to Ca2+-homeostasis and proteins implicated in various diseases including cancers and brain disorders.

scholarly journals Potential Physiological Relevance of ERAD to the Biosynthesis of GPI-Anchored Proteins in Yeast

2021 ◽  
Vol 22 (3) ◽  
pp. 1061
Author(s):  
Kunio Nakatsukasa
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Physiological Role ◽  
Misfolded Proteins ◽  
Physiological Relevance ◽  
Safe Mechanism ◽  
Fail Safe

Misfolded and/or unassembled secretory and membrane proteins in the endoplasmic reticulum (ER) may be retro-translocated into the cytoplasm, where they undergo ER-associated degradation, or ERAD. The mechanisms by which misfolded proteins are recognized and degraded through this pathway have been studied extensively; however, our understanding of the physiological role of ERAD remains limited. This review describes the biosynthesis and quality control of glycosylphosphatidylinositol (GPI)-anchored proteins and briefly summarizes the relevance of ERAD to these processes. While recent studies suggest that ERAD functions as a fail-safe mechanism for the degradation of misfolded GPI-anchored proteins, several pieces of evidence suggest an intimate interaction between ERAD and the biosynthesis of GPI-anchored proteins.

scholarly journals Endoplasmic reticulum turnover: ER-phagy and other flavors in selective and non-selective ER clearance

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 454 ◽  
Author(s):  
Ilaria Fregno ◽  
Maurizio Molinari
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Biosynthesis ◽  
Misfolded Proteins ◽  
Eukaryotic Cells ◽  
Unfolded Protein ◽  
Calcium Storage ◽  
Live Bacteria ◽  
And Function ◽  
Developmental Conditions

The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells. It is deputed to lipid and protein biosynthesis, calcium storage, and the detoxification of various exogenous and endogenous harmful compounds. ER activity and size must be adapted rapidly to environmental and developmental conditions or biosynthetic demand. This is achieved on induction of thoroughly studied transcriptional/translational programs defined as “unfolded protein responses” that increase the ER volume and the expression of ER-resident proteins regulating the numerous ER functions. Less understood are the lysosomal catabolic processes that maintain ER size at steady state, that prevent excessive ER expansion during ER stresses, or that ensure return to physiologic ER size during recovery from ER stresses. These catabolic processes may also be activated to remove ER subdomains where proteasome-resistant misfolded proteins or damaged lipids have been segregated. Insights into these catabolic mechanisms have only recently emerged with the identification of so-called ER-phagy receptors, which label specific ER subdomains for selective lysosomal delivery for clearance. Here, in eight chapters and one addendum, we comment on recent advances in ER turnover pathways induced by ER stress, nutrient deprivation, misfolded proteins, and live bacteria. We highlight the role of yeast (Atg39 and Atg40) and mammalian (FAM134B, SEC62, RTN3, and CCPG1) ER-phagy receptors and of autophagy genes in selective and non-selective catabolic processes that regulate cellular proteostasis by controlling ER size, turnover, and function.

scholarly journals The Role of the Signaling Pathways Involved in the Effects of Hydrogen Sulfide on Endoplasmic Reticulum Stress

2021 ◽  
Vol 9 ◽  
Author(s):  
Shizhen Zhao ◽  
Xinping Li ◽  
Ping Lu ◽  
Xiaotian Li ◽  
Mingfei Sun ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Hydrogen Sulfide ◽  
Signaling Pathways ◽  
Lipid Synthesis ◽  
Unfolded Proteins ◽  
Signal Molecule ◽  
Unfolded Protein ◽  
Protein Response ◽  
Er Homeostasis

Endoplasmic reticulum (ER) is a kind of organelle with multiple functions including protein synthesis, modification and folding, calcium storage, and lipid synthesis. Under stress conditions, ER homeostasis is disrupted, which is defined as ER stress (ERS). The accumulation of unfolded proteins in the ER triggers a stable signaling network named unfolded protein response (UPR). Hydrogen sulfide is an important signal molecule regulating various physiological and pathological processes. Recent studies have shown that H2S plays an important role in many diseases by affecting ERS, but its mechanism, especially the signaling pathways, is not fully understood. Therefore, in this review, we summarize the recent studies about the signaling pathways involved in the effects of H2S on ERS in diseases to provide theoretical reference for the related in-depth researches.

scholarly journals A Possible Role of ER-60 Protease in the Degradation of Misfolded Proteins in the Endoplasmic Reticulum

1995 ◽  
Vol 270 (25) ◽  
pp. 14958-14961 ◽  
Author(s):  
Mieko Otsu ◽  
Reiko Urade ◽  
Makoto Kito ◽  
Fumihiko Omura ◽  
Masakazu Kikuchi
Keyword(s):  
Endoplasmic Reticulum ◽  
Misfolded Proteins

scholarly journals EDEM1 Drives Misfolded Protein Degradation via ERAD and Exploits ER-Phagy as Back-Up Mechanism When ERAD Is Impaired

2020 ◽  
Vol 21 (10) ◽  
pp. 3468 ◽  
Author(s):  
Marioara Chiritoiu ◽  
Gabriela N. Chiritoiu ◽  
Cristian V. A. Munteanu ◽  
Florin Pastrama ◽  
N. Erwin Ivessa ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Endoplasmic Reticulum ◽  
Protein Degradation ◽  
Protein Interaction ◽  
Proteasomal Degradation ◽  
Misfolded Proteins ◽  
Misfolded Protein ◽  
Protein Protein Interaction ◽  
Pathological Conditions ◽  
Er Homeostasis

Endoplasmic reticulum (ER)-associated degradation (ERAD) is the main mechanism of targeting ER proteins for degradation to maintain homeostasis, and perturbations of ERAD lead to pathological conditions. ER-degradation enhancing α-mannosidase-like (EDEM1) was proposed to extract terminally misfolded proteins from the calnexin folding cycle and target them for degradation by ERAD. Here, using mass-spectrometry and biochemical methods, we show that EDEM1 is found in auto-regulatory complexes with ERAD components. Moreover, the N-terminal disordered region of EDEM1 mediates protein–protein interaction with misfolded proteins, whilst the absence of this domain significantly impairs their degradation. We also determined that overexpression of EDEM1 can induce degradation, even when proteasomal activity is severely impaired, by promoting the formation of aggregates, which can be further degraded by autophagy. Therefore, we propose that EDEM1 maintains ER homeostasis and mediates ERAD client degradation via autophagy when either dislocation or proteasomal degradation are impaired.

scholarly journals Dnj1 Promotes Virulence in Cryptococcus neoformans by Maintaining Robust Endoplasmic Reticulum Homeostasis Under Temperature Stress

2021 ◽  
Vol 12 ◽  
Author(s):  
Linda C. Horianopoulos ◽  
Christopher W. J. Lee ◽  
Guanggan Hu ◽  
Mélissa Caza ◽  
James W. Kronstad
Keyword(s):  
Endoplasmic Reticulum ◽  
Cryptococcus Neoformans ◽  
Virulence Factors ◽  
Fungal Pathogens ◽  
Elevated Temperatures ◽  
Mammalian Host ◽  
Human Body Temperature ◽  
J Domain ◽  
Er Homeostasis

The capacity of opportunistic fungal pathogens such as Cryptococcus neoformans to cause disease is dependent on their ability to overcome an onslaught of stresses including elevated temperature under mammalian host conditions. Protein chaperones and co-chaperones play key roles in thermotolerance. In this study, we characterized the role of the endoplasmic reticulum (ER) J-domain containing co-chaperone, Dnj1, in the virulence of C. neoformans. A strain expressing a Dnj1-GFP fusion protein was used to confirm localization to the ER, and a dnj1∆ deletion mutant was shown to be hypersensitive to the ER stress caused by tunicamycin (TM) or 4μ8C. Dnj1 and another ER chaperone, calnexin were found to coordinately maintain ER homeostasis and contribute to maintenance of cell wall architecture. Dnj1 also contributed to thermotolerance and increased in abundance at elevated temperatures representative of febrile patients (e.g., 39°C) thus highlighting its role as a temperature-responsive J domain protein. The elaboration of virulence factors such as the polysaccharide capsule and extracellular urease activity were also markedly impaired in the dnj1∆ mutant when induced at human body temperature (i.e., 37°C). These virulence factors are immunomodulatory and, indeed, infection with the dnj1∆ mutant revealed impaired induction of the cytokines IL-6, IL-10, and MCP-1 in the lungs of mice compared to infection with wild type or complemented strains. The dnj1∆ mutant also had attenuated virulence in an intranasal murine model of cryptococcosis. Altogether, our data indicate that Dnj1 is crucial for survival and virulence factor production at elevated temperatures. The characterization of this co-chaperone also highlights the importance of maintaining homeostasis in the ER for the pathogenesis of C. neoformans.

scholarly journals Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Shengjie Yang ◽  
Min Wu ◽  
Xiaoya Li ◽  
Ran Zhao ◽  
Yixi Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein ◽  
Atherosclerotic Lesions ◽  
Different Types ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
Progression Of Atherosclerosis

Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis and related cardiovascular diseases (CVDs). It occurs due to various pathological factors that interfere with ER homeostasis, resulting in the accumulation of unfolded or misfolded proteins in the ER lumen, thereby causing ER dysfunction. Here, we discuss the role of ER stress in different types of cells in atherosclerotic lesions. This discussion includes the activation of apoptotic and inflammatory pathways induced by prolonged ER stress, especially in advanced lesional macrophages and endothelial cells (ECs), as well as common atherosclerosis-related ER stressors in different lesional cells, which all contribute to the clinical progression of atherosclerosis. In view of the important role of ER stress and the unfolded protein response (UPR) signaling pathways in atherosclerosis and CVDs, targeting these processes to reduce ER stress may be a novel therapeutic strategy.

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