scholarly journals Post-translational modifications of Hsp90 and translating the chaperone code

2020 ◽  
Vol 295 (32) ◽  
pp. 11099-11117 ◽  
Author(s):  
Sarah J. Backe ◽  
Rebecca A. Sager ◽  
Mark R. Woodford ◽  
Alan M. Makedon ◽  
Mehdi Mollapour
Keyword(s):  
Protein Complexes ◽  
Cell Cycle Control ◽  
Heat Shock Protein 90 ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Chaperone Function ◽  
Short Period ◽  
Evolutionarily Conserved ◽  
Hsp90 Chaperone ◽  
The Stability

Cells have a remarkable ability to synthesize large amounts of protein in a very short period of time. Under these conditions, many hydrophobic surfaces on proteins may be transiently exposed, and the likelihood of deleterious interactions is quite high. To counter this threat to cell viability, molecular chaperones have evolved to help nascent polypeptides fold correctly and multimeric protein complexes assemble productively, while minimizing the danger of protein aggregation. Heat shock protein 90 (Hsp90) is an evolutionarily conserved molecular chaperone that is involved in the stability and activation of at least 300 proteins, also known as clients, under normal cellular conditions. The Hsp90 clients participate in the full breadth of cellular processes, including cell growth and cell cycle control, signal transduction, DNA repair, transcription, and many others. Hsp90 chaperone function is coupled to its ability to bind and hydrolyze ATP, which is tightly regulated both by co-chaperone proteins and post-translational modifications (PTMs). Many reported PTMs of Hsp90 alter chaperone function and consequently affect myriad cellular processes. Here, we review the contributions of PTMs, such as phosphorylation, acetylation, SUMOylation, methylation, O-GlcNAcylation, ubiquitination, and others, toward regulation of Hsp90 function. We also discuss how the Hsp90 modification state affects cellular sensitivity to Hsp90-targeted therapeutics that specifically bind and inhibit its chaperone activity. The ultimate challenge is to decipher the comprehensive and combinatorial array of PTMs that modulate Hsp90 chaperone function, a phenomenon termed the “chaperone code.”

scholarly journals Hsp90 chaperone code and the tumor suppressor VHL cooperatively regulate the mitotic checkpoint

2021 ◽  
Author(s):  
Mark R. Woodford ◽  
Sarah J. Backe ◽  
Laura A. Wengert ◽  
Diana M. Dunn ◽  
Dimitra Bourboulia ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Translational Regulation ◽  
Heat Shock Protein 90 ◽  
Mitotic Checkpoint ◽  
Vital Role ◽  
Independent Manner ◽  
Von Hippel Lindau ◽  
Chaperone Function ◽  
Hsp90 Chaperone ◽  
The Stability

AbstractHeat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes that plays a vital role in protecting and maintaining the functional integrity of deregulated signaling proteins in tumors. We have previously reported that the stability and activity of the mitotic checkpoint kinase Mps1 depend on Hsp90. In turn, Mps1-mediated phosphorylation Hsp90 regulates its chaperone function and is essential for the mitotic arrest. Cdc14-assisted dephosphorylation of Hsp90 is vital for the mitotic exit. Post-translational regulation of Hsp90 function is also known as the Hsp90 “Chaperone Code.” Here, we demonstrate that only the active Mps1 is ubiquitinated on K86, K827, and K848 by the tumor suppressor von Hippel-Lindau (VHL) containing E3 enzyme, in a prolyl hydroxylation-independent manner and degraded in the proteasome. Furthermore, we show that this process regulates cell exit from the mitotic checkpoint. Collectively, our data demonstrates an interplay between the Hsp90 chaperone and VHL degradation machinery in regulating mitosis.

scholarly journals HSP90 is a chaperone for DLK and is required for axon injury signaling

2018 ◽  
Vol 115 (42) ◽  
pp. E9899-E9908 ◽  
Author(s):  
Scott Karney-Grobe ◽  
Alexandra Russo ◽  
Erin Frey ◽  
Jeffrey Milbrandt ◽  
Aaron DiAntonio
Keyword(s):  
Leucine Zipper ◽  
Axon Regeneration ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Loss Of Function ◽  
Hsp90 Inhibition ◽  
Axon Injury ◽  
Evolutionarily Conserved ◽  
The Stability

Peripheral nerve injury induces a robust proregenerative program that drives axon regeneration. While many regeneration-associated genes are known, the mechanisms by which injury activates them are less well-understood. To identify such mechanisms, we performed a loss-of-function pharmacological screen in cultured adult mouse sensory neurons for proteins required to activate this program. Well-characterized inhibitors were present as injury signaling was induced but were removed before axon outgrowth to identify molecules that block induction of the program. Of 480 compounds, 35 prevented injury-induced neurite regrowth. The top hits were inhibitors to heat shock protein 90 (HSP90), a chaperone with no known role in axon injury. HSP90 inhibition blocks injury-induced activation of the proregenerative transcription factor cJun and several regeneration-associated genes. These phenotypes mimic loss of the proregenerative kinase, dual leucine zipper kinase (DLK), a critical neuronal stress sensor that drives axon degeneration, axon regeneration, and cell death. HSP90 is an atypical chaperone that promotes the stability of signaling molecules. HSP90 and DLK show two hallmarks of HSP90–client relationships: (i) HSP90 binds DLK, and (ii) HSP90 inhibition leads to rapid degradation of existing DLK protein. Moreover, HSP90 is required for DLK stability in vivo, where HSP90 inhibitor reduces DLK protein in the sciatic nerve. This phenomenon is evolutionarily conserved in Drosophila. Genetic knockdown of Drosophila HSP90, Hsp83, decreases levels of Drosophila DLK, Wallenda, and blocks Wallenda-dependent synaptic terminal overgrowth and injury signaling. Our findings support the hypothesis that HSP90 chaperones DLK and is required for DLK functions, including proregenerative axon injury signaling.

HDAC6 inhibition enhances 17-AAG–mediated abrogation of hsp90 chaperone function in human leukemia cells

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 1886-1893 ◽  
Author(s):  
Rekha Rao ◽  
Warren Fiskus ◽  
Yonghua Yang ◽  
Pearl Lee ◽  
Rajeshree Joshi ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Hdac Inhibitors ◽  
Heat Shock Protein 90 ◽  
K562 Cells ◽  
Proteasomal Degradation ◽  
Atp Binding ◽  
Human Leukemia ◽  
Histone Deacetylase 6 ◽  
Chaperone Function ◽  
Hsp90 Chaperone

Abstract Histone deacetylase 6 (HDAC6) is a heat shock protein 90 (hsp90) deacetylase. Treatment with pan-HDAC inhibitors or depletion of HDAC6 by siRNA induces hyperacetylation and inhibits ATP binding and chaperone function of hsp90. Treatment with 17-allylamino-demothoxy geldanamycin (17-AAG) also inhibits ATP binding and chaperone function of hsp90, resulting in polyubiquitylation and proteasomal degradation of hsp90 client proteins. In this study, we determined the effect of hsp90 hyperacetylation on the anti-hsp90 and antileukemia activity of 17-AAG. Hyperacetylation of hsp90 increased its binding to 17-AAG, as well as enhanced 17-AAG–mediated attenuation of ATP and the cochaperone p23 binding to hsp90. Notably, treatment with 17-AAG alone also reduced HDAC6 binding to hsp90 and induced hyperacetylation of hsp90. This promoted the proteasomal degradation of HDAC6. Cotreatment with 17-AAG and siRNA to HDAC6 induced more inhibition of hsp90 chaperone function and depletion of BCR-ABL and c-Raf than treatment with either agent alone. In addition, cotreatment with 17-AAG and tubacin augmented the loss of survival of K562 cells and viability of primary acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) samples. These findings demonstrate that HDAC6 is an hsp90 client protein and hyperacetylation of hsp90 augments the anti-hsp90 and antileukemia effects of 17-AAG.

NuA4 and SWR1-C: two chromatin-modifying complexes with overlapping functions and componentsThis paper is one of a selection of papers published in this Special Issue, entitled 30th Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal's usual peer review process.

2009 ◽  
Vol 87 (5) ◽  
pp. 799-815 ◽  
Author(s):  
Phoebe Y.T. Lu ◽  
Nancy Lévesque ◽  
Michael S. Kobor
Keyword(s):  
Chromatin Structure ◽  
Protein Complexes ◽  
Peer Review Process ◽  
Histone Variant ◽  
Chromatin Remodelling ◽  
Cellular Processes ◽  
Evolutionarily Conserved ◽  
And Function ◽  
Histone Deposition ◽  
Chemical Groups

Chromatin structure is important for the compaction of eukaryotic genomes, thus chromatin modifications play a fundamental role in regulating many cellular processes. The coordinated activities of various chromatin-remodelling and -modifying complexes are crucial in maintaining distinct chromatin neighbourhoods, which in turn ensure appropriate gene expression, as well as DNA replication, repair, and recombination. SWR1-C is an ATP-dependent histone deposition complex for the histone variant H2A.Z, whereas NuA4 is a histone acetyltransferase for histones H4, H2A, and H2A.Z. Together the NuA4 and SWR1-C chromatin-modifying complexes alter the chromatin structure through 3 distinct modifications in yeast: post-translational addition of chemical groups, ATP-dependent chromatin remodelling, and histone variant incorporation. These 2 multi-protein complexes share 4 subunits and function together to regulate the circuitry of H2A.Z biology. The components and functions of both multi-protein complexes are evolutionarily conserved and play important roles in multi-cellular development and cellular differentiation in higher eukaryotes. This review will summarize recent findings about NuA4 and SWR1-C and will focus on the connection between these complexes by investigating their physical and functional interactions through eukaryotic evolution.

scholarly journals The formation of a fuzzy complex in the negative arm regulates the robustness of the circadian clock.

2022 ◽  
Author(s):  
Meaghan S. Jankowski ◽  
Daniel Griffith ◽  
Divya G. Shastry ◽  
Jacqueline F. Pelham ◽  
Garrett M. Ginell ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Electrostatic Interactions ◽  
Motif Discovery ◽  
Rational Design ◽  
Protein Complexes ◽  
Linear Motif ◽  
Cellular Processes ◽  
Evolutionarily Conserved ◽  
Positively Charged ◽  
Clock Protein

The circadian clock times cellular processes to the day/night cycle via a Transcription-Translation negative Feedback Loop (TTFL). However, a mechanistic understanding of the negative arm in both the timing of the TTFL and its control of output is lacking. We posited that the formation of negative-arm protein complexes was fundamental to clock regulation stemming from the negative arm. Using a modified peptide microarray approach termed Linear motif discovery using rational design (LOCATE), we characterized the interaction of the disordered negative-arm clock protein FREQUENCY to its partner protein FREQUENCY-Interacting RNA helicase. LOCATE identified a specific Short Linear Motif (SLiM) and interaction hotspot as well as positively charged islands that mediate electrostatic interactions, suggesting a model where negative arm proteins form a fuzzy complex essential for clock timing and robustness. Further analysis revealed that the positively charged islands were an evolutionarily conserved feature in higher eukaryotes and contributed to proper clock function.

Post-translational modifications and stabilization of microtubules regulate transport of viral factors during infections

2021 ◽  
Vol 49 (4) ◽  
pp. 1735-1748
Author(s):  
Silvia Requena ◽  
Francisco Sánchez-Madrid ◽  
Noa B. Martín-Cófreces
Keyword(s):  
Immune Responses ◽  
Immune Cells ◽  
Building Blocks ◽  
Cell Types ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Associated Proteins ◽  
The Stability ◽  
Different Characteristics ◽  
Β Tubulin

Tubulin post-translational modifications (PTMs) constitute a source of diversity for microtubule (MT) functions, in addition to the different isotypes of α and β-tubulin acting as building blocks of MTs. Also, MT-associated proteins (MAPs) confer different characteristics to MTs. The combination of all these factors regulates the stability of these structures that act as rails to transport organelles within the cell, facilitating the association of motor complexes. All these functions are involved in crucial cellular processes in most cell types, ranging from spindle formation in mitosis to the defense against incoming cellular threats during phagocytosis mediated by immune cells. The regulation of MT dynamics through tubulin PTMs has evolved to depend on many different factors that act in a complex orchestrated manner. These tightly regulated processes are particularly relevant during the induction of effective immune responses against pathogens. Viruses have proved not only to hijack MTs and MAPs in order to favor an efficient infection, but also to induce certain PTMs that improve their cellular spread and lead to secondary consequences of viral processes. In this review, we offer a perspective on relevant MT-related elements exploited by viruses.

An Overview of HDAC Inhibitors and their Synthetic Routes

2019 ◽  
Vol 19 (12) ◽  
pp. 1005-1040 ◽  
Author(s):  
Xiaopeng Peng ◽  
Guochao Liao ◽  
Pinghua Sun ◽  
Zhiqiang Yu ◽  
Jianjun Chen
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Cell Cycle Control ◽  
Hdac Inhibitors ◽  
Cancer Therapeutics ◽  
Cellular Processes ◽  
Chaperone Function ◽  
Damage Repair ◽  
Synthetic Routes

Epigenetics play a key role in the origin, development and metastasis of cancer. Epigenetic processes include DNA methylation, histone acetylation, histone methylation, and histone phosphorylation, among which, histone acetylation is the most common one that plays important roles in the regulation of normal cellular processes, and is controlled by histone deacetylases (HDACs) and histone acetyltransferases (HATs). HDACs are involved in the regulation of many key cellular processes, such as DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function, and can lead to oncogene activation. As a result, HDACs are considered to be an excellent target for anti-cancer therapeutics like histone deacetylase inhibitors (HDACi) which have attracted much attention in the last decade. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. The primary purpose of this paper is to summarize recent HDAC inhibitors and the synthetic routes as well as to discuss the direction for the future development of new HDAC inhibitors.

scholarly journals Acute Myeloid Leukemia-Related Proteins Modified by Ubiquitin and Ubiquitin-like Proteins

2022 ◽  
Vol 23 (1) ◽  
pp. 514
Author(s):  
Sang-Soo Park ◽  
Kwang-Hyun Baek
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Cycle Control ◽  
Critical Role ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Current Review ◽  
Related Proteins ◽  
Acute Myeloid

Acute myeloid leukemia (AML), the most common form of an acute leukemia, is a malignant disorder of stem cell precursors of the myeloid lineage. Ubiquitination is one of the post-translational modifications (PTMs), and the ubiquitin-like proteins (Ubls; SUMO, NEDD8, and ISG15) play a critical role in various cellular processes, including autophagy, cell-cycle control, DNA repair, signal transduction, and transcription. Also, the importance of Ubls in AML is increasing, with the growing research defining the effect of Ubls in AML. Numerous studies have actively reported that AML-related mutated proteins are linked to Ub and Ubls. The current review discusses the roles of proteins associated with protein ubiquitination, modifications by Ubls in AML, and substrates that can be applied for therapeutic targets in AML.

scholarly journals Applying the auxin-inducible degradation (AID) system for rapid protein depletion in mammalian cells

2017 ◽  
Author(s):  
Bramwell G. Lambrus ◽  
Tyler C. Moyer ◽  
Andrew J. Holland
Keyword(s):  
Mammalian Cells ◽  
Fluorescent Proteins ◽  
Protein Complexes ◽  
Successful Implementation ◽  
Protein Depletion ◽  
Cellular Processes ◽  
Ubiquitin Ligase Complex ◽  
Short Period ◽  
Subsequent Degradation ◽  
Genomic Locations

AbstractThe ability to deplete a protein of interest is critical for dissecting cellular processes. Traditional methods of protein depletion are often slow-acting, which can be problematic when characterizing a cellular process that occurs within a short period of time. Furthermore, these methods are usually not reversible. Recent advances to achieve protein depletion function by inducibly trafficking proteins of interest to an endogenous E3 ubiquitin ligase complex to promote ubiquitination and subsequent degradation by the proteasome. One of these systems, the auxin-inducible degron (AID) system, has been shown to permit rapid and inducible degradation of AID-tagged target proteins in mammalian cells. The AID system can control the abundance of a diverse set of cellular proteins, including those contained within protein complexes, and is active in all phases of the cell cycle. Here we discuss considerations for the successful implementation of the AID system and describe a protocol using CRISPR/Cas9 to achieve bi-allelic insertion of an AID degron in human cells. This method can also be adapted to insert other tags, such as fluorescent proteins, at defined genomic locations.

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