Faculty Opinions recommendation of Spatially distinct pools of TORC1 balance protein homeostasis.

Introduction:Multiple myeloma (MM) cells accumulate in the bone marrow and produce enormous quantities of immunoglobulins, causing endoplasmatic reticulum stress and activation of protein handling machinery, such as heat shock protein response, autophagy and unfolded protein response (UPR).Methods:We evaluated cell lines viability after treatment with bortezomib (B) in combination with HSP70 (VER-15508) and autophagy (SBI-0206965) or UPR (STF- 083010) inhibitors.Results:For RPMI-8226, after 72 hours of treatment with B+VER+STF or B+VER+SBI, we observed 15% of viable cells, but treatment with B alone was better (90% of cell death). For U266, treatment with B+VER+STF or with B+VER+SBI for 72 hours resulted in 20% of cell viability and both treatments were better than treatment with B alone (40% of cell death). After both triplet combinations, RPMI-8226 and U266 presented the overexpression of XBP-1 UPR protein, suggesting that it is acting as a compensatory mechanism, in an attempt of the cell to handle the otherwise lethal large amount of immunoglobulin overload.Conclusion:Our in vitro results provide additional evidence that combinations of protein homeostasis inhibitors might be explored as treatment options for MM.

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PROTEOSTASIS: A European Network to Break Barriers and Integrate Science on Protein Homeostasis

Trends in Biochemical Sciences ◽

10.1016/j.tibs.2019.01.007 ◽

2019 ◽

Vol 44 (5) ◽

pp. 383-387 ◽

Cited By ~ 3

Author(s):

Nico Dissmeyer ◽

Olivier Coux ◽

Manuel S. Rodriguez ◽

Rosa Barrio

Keyword(s):

Protein Homeostasis ◽

European Network ◽

Integrate Science

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RSF1 in cancer: interactions and functions

Cancer Cell International ◽

10.1186/s12935-021-02012-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Guiyang Cai ◽

Qing Yang ◽

Wei Sun

Keyword(s):

Optimal Level ◽

Cell Cycle Checkpoint ◽

Protein Homeostasis ◽

Clinical Value ◽

Cancer Proliferation ◽

Poor Overall Survival ◽

Cyclin E1 ◽

Spacing Factor ◽

Cycle Checkpoint ◽

Cancer Types

AbstractRSF1, remodelling and spacing factor 1, is an important interphase centromere protein and is overexpressed in many types of cancers and correlated with poor overall survival. RSF1 has functions mainly in maintaining chromosome stability, facilitating DNA repair, maintaining the protein homeostasis of RSF1 and suppressing the transcription of some oncogenes when RSF1 protein is expressed at an optimal level; however, RSF1 overexpression facilitates drug resistance and cell cycle checkpoint inhibition to prompt cancer proliferation and survival. The RSF1 expression level and gene background are crucial for RSF1 functions, which may explain why RSF1 has different functions in different cancer types. This review summarizes the functional domains of RSF1, the overexpression status of RSF1 and SNF2H in cancer based on the TCGA and GTEX databases, the cancer-related functions of RSF1 in interacting with H2Aub, HDAC1, CENP-A, PLK1, ATM, CENP-S, SNF2H, HBX, BubR1, cyclin E1, CBP and NF-κB and the potential clinical value of RSF1, which will lay a theoretical foundation for the structural biology study of RSF1 and application of RSF1 inhibitors, truncated RSF1 proteins and SNF2H inhibitors in the treatment of RSF1-overexpressing tumours.

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DNA damage and regulation of protein homeostasis

DNA Repair ◽

10.1016/j.dnarep.2021.103155 ◽

2021 ◽

Vol 105 ◽

pp. 103155

Author(s):

Tanya T. Paull

Keyword(s):

Dna Damage ◽

Protein Homeostasis

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Deubiquitylating enzymes in neuronal health and disease

Cell Death and Disease ◽

10.1038/s41419-020-03361-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Fatima Amer-Sarsour ◽

Alina Kordonsky ◽

Yevgeny Berdichevsky ◽

Gali Prag ◽

Avraham Ashkenazi

Keyword(s):

Human Brain ◽

Neurodegenerative Disorders ◽

Structure And Function ◽

Pivotal Role ◽

Protein Homeostasis ◽

Neuronal Function ◽

Health And Disease ◽

And Function

AbstractUbiquitylation and deubiquitylation play a pivotal role in protein homeostasis (proteostasis). Proteostasis shapes the proteome landscape in the human brain and its impairment is linked to neurodevelopmental and neurodegenerative disorders. Here we discuss the emerging roles of deubiquitylating enzymes in neuronal function and survival. We provide an updated perspective on the genetics, physiology, structure, and function of deubiquitylases in neuronal health and disease.

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Structural basis of Naa20 activity towards a canonical NatB substrate

Communications Biology ◽

10.1038/s42003-020-01546-4 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Dominik Layer ◽

Jürgen Kopp ◽

Miriam Fontanillo ◽

Maja Köhn ◽

Karine Lapouge ◽

...

Keyword(s):

Crystal Structure ◽

Drug Development ◽

Catalytic Mechanism ◽

Peptide Binding ◽

Competitive Inhibitor ◽

Structural Basis ◽

Substrate Affinity ◽

Protein Homeostasis ◽

Auxiliary Subunit

AbstractN-terminal acetylation is one of the most common protein modifications in eukaryotes and is carried out by N-terminal acetyltransferases (NATs). It plays important roles in protein homeostasis, localization, and interactions and is linked to various human diseases. NatB, one of the major co-translationally active NATs, is composed of the catalytic subunit Naa20 and the auxiliary subunit Naa25, and acetylates about 20% of the proteome. Here we show that NatB substrate specificity and catalytic mechanism are conserved among eukaryotes, and that Naa20 alone is able to acetylate NatB substrates in vitro. We show that Naa25 increases the Naa20 substrate affinity, and identify residues important for peptide binding and acetylation activity. We present the first Naa20 crystal structure in complex with the competitive inhibitor CoA-Ac-MDEL. Our findings demonstrate how Naa20 binds its substrates in the absence of Naa25 and support prospective endeavors to derive specific NAT inhibitors for drug development.

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Immunoproteasome Function in Normal and Malignant Hematopoiesis

Cells ◽

10.3390/cells10071577 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1577

Author(s):

Nuria Tubío-Santamaría ◽

Frédéric Ebstein ◽

Florian H. Heidel ◽

Elke Krüger

Keyword(s):

Proteasome Inhibition ◽

Ubiquitin Proteasome System ◽

Hematologic Malignancies ◽

Protein Homeostasis ◽

Efficacy And Safety ◽

Hematopoietic System ◽

Oxidized Proteins ◽

Attractive Therapeutic Target ◽

Ubiquitin Proteasome ◽

Early Phases

The ubiquitin–proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.

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