Heat shock protein 90 maintains the stability and function of transcription factor Broad Z7 by interacting with its Broad-Complex-Tramtrack-Bric-a-brac domain

2014 ◽  
Vol 23 (6) ◽  
pp. 720-732 ◽  
Author(s):  
M.-J. Cai ◽  
X.-R. Li ◽  
X.-Y. Pei ◽  
W. Liu ◽  
J.-X. Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
The Stability ◽  
And Function ◽  
Broad Complex

scholarly journals Heat shock protein 90: its inhibition and function

2017 ◽  
Vol 373 (1738) ◽  
pp. 20160527 ◽  
Author(s):  
Abbey D. Zuehlke ◽  
Michael A. Moses ◽  
Len Neckers
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Bacterial Infections ◽  
Large Range ◽  
Heat Shock Protein 90 ◽  
Protein Maturation ◽  
Theme Issue ◽  
Shock Proteins ◽  
And Function ◽  
Dynamic Interplay

The molecular chaperone heat shock protein 90 (Hsp90) facilitates metastable protein maturation, stabilization of aggregation-prone proteins, quality control of misfolded proteins and assists in keeping proteins in activation-competent conformations. Proteins that rely on Hsp90 for function are delivered to Hsp90 utilizing a co-chaperone–assisted cycle. Co-chaperones play a role in client transfer to Hsp90, Hsp90 ATPase regulation and stabilization of various Hsp90 conformational states. Many of the proteins chaperoned by Hsp90 (Hsp90 clients) are essential for the progression of various diseases, including cancer, Alzheimer's disease and other neurodegenerative diseases, as well as viral and bacterial infections. Given the importance of these clients in different diseases and their dynamic interplay with the chaperone machinery, it has been suggested that targeting Hsp90 and its respective co-chaperones may be an effective method for combating a large range of illnesses. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

scholarly journals Heat Shock Protein 90 Ensures Efficient Mumps Virus Replication by Assisting with Viral Polymerase Complex Formation

2017 ◽  
Vol 91 (6) ◽  
Author(s):  
Hiroshi Katoh ◽  
Toru Kubota ◽  
Yuichiro Nakatsu ◽  
Maino Tahara ◽  
Minoru Kidokoro ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Measles Virus ◽  
Heat Shock Protein 90 ◽  
Mumps Virus ◽  
Viral Polymerase ◽  
Polymerase Complex ◽  
L Protein ◽  
Hsp90 Activity ◽  
The Stability

ABSTRACT Paramyxoviral RNAs are synthesized by a viral RNA-dependent RNA polymerase (RdRp) consisting of the large (L) protein and its cofactor phosphoprotein (P protein). The L protein is a multifunctional protein that catalyzes RNA synthesis, mRNA capping, and mRNA polyadenylation. Growing evidence shows that the stability of several paramyxovirus L proteins is regulated by heat shock protein 90 (Hsp90). In this study, we demonstrated that Hsp90 activity was important for mumps virus (MuV) replication. The Hsp90 activity was required for L-protein stability and activity because an Hsp90-specific inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), destabilized the MuV L protein and suppressed viral RNA synthesis. However, once the L protein formed a mature polymerase complex with the P protein, Hsp90 activity was no longer required for the stability and activity of the L protein. When the Hsp90 activity was inhibited, the MuV L protein was degraded through the CHIP (C terminus of Hsp70-interacting protein)-mediated proteasomal pathway. High concentrations of 17-AAG showed strong cytotoxicity to certain cell types, but combined use of an Hsp70 inhibitor, VER155008, potentiated degradation of the L protein, allowing a sufficient reduction of 17-AAG concentration to block MuV replication with minimum cytotoxicity. Regulation of the L protein by Hsp90 and Hsp70 chaperones was also demonstrated for another paramyxovirus, the measles virus. Collectively, our data show that the Hsp90/Hsp70 chaperone machinery assists in the maturation of the paramyxovirus L protein and thereby in the formation of a mature RdRp complex and efficient viral replication. IMPORTANCE Heat shock protein 90 (Hsp90) is nearly universally required for viral protein homeostasis. Here, we report that Hsp90 activity is required for efficient propagation of mumps virus (MuV). Hsp90 functions in the maintenance of the catalytic subunit of viral polymerase, the large (L) protein, prior to formation of a mature polymerase complex with the polymerase cofactor of L, phosphoprotein. Hsp70 collaborates with Hsp90 to regulate biogenesis of the MuV L protein. The functions of these chaperones on the viral polymerase may be common among paramyxoviruses because the L protein of measles virus is also similarly regulated. Our data provide important insights into the molecular mechanisms of paramyxovirus polymerase maturation as well as a basis for the development of novel antiviral drugs.

scholarly journals HSP90: Enabler of Cancer Adaptation

2019 ◽  
Vol 3 (1) ◽  
pp. 275-297 ◽  
Author(s):  
Alex M. Jaeger ◽  
Luke Whitesell
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Model Organisms ◽  
Hsp90 Inhibitors ◽  
Mutant Proteins ◽  
High Doses ◽  
The Stability ◽  
And Function ◽  
Effective Use

The stability and function of many oncogenic mutant proteins depend on heat shock protein 90 (HSP90). This unique activity has inspired the exploration of HSP90 as an anticancer target for over two decades. Unfortunately, while clinical trials of highly optimized HSP90 inhibitors have demonstrated modest benefit for patients with advanced cancers, most commonly stabilization of disease, no HSP90 inhibitor has demonstrated sufficient efficacy to achieve FDA approval to date. This review discusses potential reasons for the limited success of these agents and how our increasingly sophisticated understanding of HSP90 suggests alternative, potentially more effective strategies for targeting it to treat cancers. First, we focus on insights gained from model organisms that suggest a fundamental role for HSP90 in supporting the adaptability and heterogeneity of cancers, key factors underlying their ability to evolve and acquire drug resistance. Second, we examine how HSP90’s role in promoting the stability of mutant proteins might be targeted in genetically unstable tumor cells to reveal their aberrant, foreign proteome to the immune system. Both of these emerging aspects of HSP90 biology suggest that the most effective use of HSP90 inhibitors may not be at high doses with the intent to kill cancer cells, but rather in combination with other molecularly targeted therapies at modest, non-heat shock-inducing exposures that limit the adaptive capacity of cancers.

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