The Unfolded Protein Response as a Guardian of the Secretory Pathway

Radanović, Toni; Ernst, Robert

doi:10.3390/cells10112965

Cited by 33 publications

(21 citation statements)

References 204 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When aggregation of misfolded proteins in the ER lumen occurs, UPR sensors detect the lesion and trigger the dissociation from Grp78. These alterations lead to the homo-dimerization and homo-oligomerization of IRE1α and PERK, respectively, and the migration of ATF6 to the Golgi apparatus, which induce the sophisticated downstream network of events [ 22 ]. The three pathways are artificially defined, and indeed a cross-interactive cascade modulating comprehensive cell responses to achieve adaption, or result in apoptosis ( Figure 1 ).…”

Section: Ers and Drug-resistance Of MMmentioning

confidence: 99%

Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?

Wang

Fan

Sun

et al. 2022

Cancers

View full text Add to dashboard Cite

Multiple myeloma (MM) is the second most common hematologic malignancy, resulting from the clonal proliferation of malignant plasma cells within the bone marrow. Despite significant advances that have been made with novel drugs over the past two decades, MM patients often develop therapy resistance, especially to bortezomib, the first-in-class proteasome inhibitor that was approved for treatment of MM. As highly secretory monoclonal protein-producing cells, MM cells are characterized by uploaded endoplasmic reticulum stress (ERS), and rely heavily on the ERS response for survival. Great efforts have been made to illustrate how MM cells adapt to therapeutic stresses through modulating the ERS response. In this review, we summarize current knowledge on the mechanisms by which ERS response pathways influence MM cell fate and response to treatment. Moreover, based on promising results obtained in preclinical studies, we discuss the prospect of applying ERS modulators to overcome drug resistance in MM.

show abstract

Section: Ers and Drug-resistance Of MMmentioning

confidence: 99%

Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?

Wang

Fan

Sun

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…LAMP2A is the rate-limiting step of CMA, as HSP70 threads the unfolded protein through its pore, into the lumen. The AKT/mTOR system regulates the phosphorylation/deactivation status of LAMP2A, increasing the stress status selectivity of Bag3–HSP70-mediated autophagy [ 85 ]. Unique to chaperone-mediated autophagy, the conditions of the docking receptor LAMP2A, the protein sequence K–F–E–R–Q (or KFERQ-like domain), and a loosely folded protein must be present for HSP70 to release the client to the lysosome.…”

Section: Protein Quality Controlmentioning

confidence: 99%

“…Regorafenib, a medication approved for colorectal cancer treatment, has been observed to indirectly obstruct autophagolysosome fusion. Successfully halting macroautophagy, teams have found that regorafenib induces apoptosis in recurrent and treatment-resistant glioblastoma multiforme [ 85 , 148 ].…”

Section: Glioblastoma As a Proteinopathymentioning

confidence: 99%

Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets

Rocchi

Wollebo

Khalili

2022

IJMS

View full text Add to dashboard Cite

Protein quality control allows eukaryotes to maintain proteostasis under the stress of constantly changing conditions. In this review, we discuss the current literature on PQC, highlighting flaws that must exist for malignancy to occur. At the nidus of PQC, the expression of BAG1-6 reflects the cell environment; each isoform directs proteins toward different, parallel branches of the quality control cascade. The sum of these branches creates a net shift toward either homeostasis or apoptosis. With an established role in ALP, Bag3 is necessary for cell survival in stress conditions including those of the cancerous niche (i.e., hypoxia, hypermutation). Evidence suggests that excessive Bag3–HSP70 activity not only sustains, but also propagates cancers. Its role is anti-apoptotic—which allows malignant cells to persist—and intercellular—with the production of infectious ‘oncosomes’ enabling cancer expansion and recurrence. While Bag3 has been identified as a key prognostic indicator in several cancer types, its investigation is limited regarding glioblastoma. The cochaperone HSP70 has been strongly linked with GBM, while ALP inhibitors have been shown to improve GBM susceptibility to chemotherapeutics. Given the highly resilient, frequently recurrent nature of GBM, the targeting of Bag3 is a necessary consideration for the successful and definitive treatment of GBM.

show abstract

“…ER stress is sensed by a sophisticated system of transmembrane proteins, the inositol requiring enzyme 1α (IRE1α), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6), which are silenced by their binding to immunoglobin binding protein (BiP), which is the ER-resident heat shock 70 protein (Hsp70) protein. Vice versa, the activation of IRE1α, PERK, and ATF6 is induced by the release of BiP from their luminal domains and even by the direct binding of misfolded proteins to the luminal domains, as has been shown for IRE1α [ 1 , 2 , 3 , 4 ]. The activation of these proteins induces different pathways of a cell’s stress response, termed the unfolded protein response (UPR).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Translation, Translocation, and Degradation of Proteins at the Membrane of the Endoplasmic Reticulum

Daverkausen-Fischer

Draga

Pröls

2022

IJMS

View full text Add to dashboard Cite

The endoplasmic reticulum (ER) of mammalian cells is the central organelle for the maturation and folding of transmembrane proteins and for proteins destined to be secreted into the extracellular space. The proper folding of target proteins is achieved and supervised by a complex endogenous chaperone machinery. BiP, a member of the Hsp70 protein family, is the central chaperone in the ER. The chaperoning activity of BiP is assisted by ER-resident DnaJ (ERdj) proteins due to their ability to stimulate the low, intrinsic ATPase activity of BiP. Besides their co-chaperoning activity, ERdj proteins also regulate and tightly control the translation, translocation, and degradation of proteins. Disturbances in the luminal homeostasis result in the accumulation of unfolded proteins, thereby eliciting a stress response, the so-called unfolded protein response (UPR). Accumulated proteins are either deleterious due to the functional loss of the respective protein and/or due to their deposition as intra- or extracellular protein aggregates. A variety of metabolic diseases are known to date, which are associated with the dysfunction of components of the chaperone machinery. In this review, we will delineate the impact of ERdj proteins in controlling protein synthesis and translocation under physiological and under stress conditions. A second aspect of this review is dedicated to the role of ERdj proteins in the ER-associated degradation pathway, by which unfolded or misfolded proteins are discharged from the ER. We will refer to some of the most prominent diseases known to be based on the dysfunction of ERdj proteins.

show abstract

The Unfolded Protein Response as a Guardian of the Secretory Pathway

Cited by 33 publications

References 204 publications

Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?

Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?

Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets

Regulation of Translation, Translocation, and Degradation of Proteins at the Membrane of the Endoplasmic Reticulum

Contact Info

Product

Resources

About