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 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 The ESCRT-0 Protein HRS Interacts with the Human T Cell Leukemia Virus Type 2 Antisense Protein APH-2 and Suppresses Viral Replication

2019 ◽  
Vol 94 (1) ◽  
Author(s):  
Fanny Martini ◽  
Coline Arone ◽  
Amy Hasset ◽  
William W. Hall ◽  
Noreen Sheehy
Keyword(s):  
T Cell ◽  
Negative Impact ◽  
Leukemia Virus ◽  
Cell Leukemia ◽  
Lysosomal Degradation ◽  
Cell Leukemia Virus Type ◽  
Escrt Machinery ◽  
Human T Cell ◽  
T Cell Leukemia Virus

ABSTRACT The divergent clinical outcomes of human T cell leukemia virus type 1 (HTLV-1) and HTLV-2 infections have been attributed to functional differences in their antisense proteins. In contrast to HTLV-1 bZIP factor (HBZ), the role of the antisense protein of HTLV-2 (APH-2) in HTLV-2 infection is poorly understood. In previous studies, we identified the endosomal sorting complex required for transport 0 (ESCRT-0) subunit HRS as a novel interaction partner of APH-2 but not HBZ. HRS is a master regulator of endosomal protein sorting for lysosomal degradation and is hijacked by many viruses to promote replication. However, no studies to date have shown a link between HTLVs and HRS. In this study, we sought to characterize the interaction between HRS and APH-2 and to investigate the impact of HRS on the life cycle of HTLV-2. We confirmed a direct specific interaction between APH-2 and HRS and showed that the CC2 domain of HRS and the N-terminal domain of APH-2 mediate their interaction. We demonstrated that HRS recruits APH-2 to early endosomes, possibly furnishing an entry route into the endosomal/lysosomal pathway. We demonstrated that inhibition of this pathway using either bafilomycin or HRS overexpression substantially extends the half-life of APH-2 and stabilizes Tax2B expression levels. We found that HRS enhances Tax2B-mediated long terminal repeat (LTR) activation, while depletion of HRS enhances HTLV-2 production and release, indicating that HRS may have a negative impact on HTLV-2 replication. Overall, our study provides important new insights into the role of the ESCRT-0 HRS protein, and by extension the ESCRT machinery and the endosomal/lysosomal pathway, in HTLV-2 infection. IMPORTANCE While APH-2 is the only viral protein consistently expressed in infected carriers, its role in HTLV-2 infection is poorly understood. In this study, we characterized the interaction between the ESCRT-0 component HRS and APH-2 and explored the role of HRS in HTLV-2 replication. HRS is a master regulator of protein sorting for lysosomal degradation, a feature that is manipulated by several viruses to promote replication. Unexpectedly, we found that HRS targets APH-2 and possibly Tax2B for lysosomal degradation and has an overall negative impact on HTLV-2 replication and release. The negative impact of interactions between HTLV-2 regulatory proteins and HRS, and by extension the ESCRT machinery, may represent an important strategy used by HTLV-2 to limit virus production and to promote persistence, features that may contribute to the limited pathogenic potential of this infection.

scholarly journals Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1513
Author(s):  
Chee Wai Fhu ◽  
Azhar Ali
Keyword(s):  
Protein Quality ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Eukaryotic Cells ◽  
Lysosomal Degradation ◽  
Polyubiquitin Chains ◽  
Protein Levels ◽  
Cellular Processes ◽  
Ubiquitin Proteasome

The ubiquitin proteasome system (UPS) governs the non-lysosomal degradation of oxidized, damaged, or misfolded proteins in eukaryotic cells. This process is tightly regulated through the activation and transfer of polyubiquitin chains to target proteins which are then recognized and degraded by the 26S proteasome complex. The role of UPS is crucial in regulating protein levels through degradation to maintain fundamental cellular processes such as growth, division, signal transduction, and stress response. Dysregulation of the UPS, resulting in loss of ability to maintain protein quality through proteolysis, is closely related to the development of various malignancies and tumorigenesis. Here, we provide a comprehensive general overview on the regulation and roles of UPS and discuss functional links of dysregulated UPS in human malignancies. Inhibitors developed against components of the UPS, which include U.S. Food and Drug Administration FDA-approved and those currently undergoing clinical trials, are also presented in this review.

scholarly journals Role of a ribosome-associated E3 ubiquitin ligase in protein quality control

Nature ◽  
2010 ◽  
Vol 467 (7314) ◽  
pp. 470-473 ◽  
Author(s):  
Mario H. Bengtson ◽  
Claudio A. P. Joazeiro
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
E3 Ubiquitin Ligase ◽  
Protein Quality Control

scholarly journals Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ariadna Recasens ◽  
Sean J. Humphrey ◽  
Michael Ellis ◽  
Monira Hoque ◽  
Ramzi H. Abbassi ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Cyclin B ◽  
Anaphase Promoting Complex ◽  
Mechanistic Studies ◽  
Glioblastoma Cells ◽  
Cycle Arrest ◽  
Dual Specificity ◽  
Rb Pathway ◽  
High Doses

AbstractBoth tumour suppressive and oncogenic functions have been reported for dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Herein, we performed a detailed investigation to delineate the role of DYRK1A in glioblastoma. Our phosphoproteomic and mechanistic studies show that DYRK1A induces degradation of cyclin B by phosphorylating CDC23, which is necessary for the function of the anaphase-promoting complex, a ubiquitin ligase that degrades mitotic proteins. DYRK1A inhibition leads to the accumulation of cyclin B and activation of CDK1. Importantly, we established that the phenotypic response of glioblastoma cells to DYRK1A inhibition depends on both retinoblastoma (RB) expression and the degree of residual DYRK1A activity. Moderate DYRK1A inhibition leads to moderate cyclin B accumulation, CDK1 activation and increased proliferation in RB-deficient cells. In RB-proficient cells, cyclin B/CDK1 activation in response to DYRK1A inhibition is neutralized by the RB pathway, resulting in an unchanged proliferation rate. In contrast, complete DYRK1A inhibition with high doses of inhibitors results in massive cyclin B accumulation, saturation of CDK1 activity and cell cycle arrest, regardless of RB status. These findings provide new insights into the complexity of context-dependent DYRK1A signalling in cancer cells.

Role of ubiquitin ligase PELI1 deficiency in atherosclerosis

2021 ◽  
Vol 331 ◽  
pp. e80
Author(s):  
K.T. Miteva ◽  
F. Burger ◽  
D. Baptista ◽  
A. Roth ◽  
F. Mach ◽  
...  
Keyword(s):  
Ubiquitin Ligase

scholarly journals TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

2021 ◽  
Author(s):  
Xu Zhou ◽  
Xiongjin Chen ◽  
Tingting Hong ◽  
Miaoping Zhang ◽  
Yujie Cai ◽  
...  
Keyword(s):  
Quality Control ◽  
Cognitive Impairment ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Research Progress ◽  
Repeat Domain ◽  
Ubiquitin Proteasome ◽  
Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

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