Selecting the first chemical molecule inhibitor of HSP110 for colorectal cancer therapy

Gozzi, Gustavo Jabor; González, Daniel H.; Boudesco, Christophe; Dias, A.; Gotthard, Guillaume; Uyanik, Burhan; Dondaine, Lucile; Marcion, Guillaume; Hermetet, François; Denis, Camille; Hardy, Laurianne; Suzanne, Peggy; Douhard, Romain; Jégo, Gaëtan; Dubrez, Laurence; Demidov, Oleg N.; Neiers, Fabrice; Briand, Loı̈c; Santos, Jana Sopková−de Oliveira; Voisin‐Chiret, Anne Sophie; Garrido, Carmen

doi:10.1038/s41418-019-0343-4

Cited by 44 publications

(45 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The HSP110-type NEFs are a subfamily of heat shock proteins within the HSP70 superfamily, and thus share structural similarities with HSP70 [174][175][176]. Once activated by ATP [177], the HSP110 NBD wraps around the HSP70 NBD, which imposes the ADP-releasing conformational change [87,178,179].…”

Section: Regulation Of Chaperone Activitymentioning

confidence: 99%

“…However, as HSP110 is able to bind unfolded proteins through its SBD [181], its presence prevents protein misfolding and aggregation. Accordingly, HSP110 expression is induced upon stress signaling [120] and currently, an inhibitor of HSP110, foldamer 33, is being tested as a potential anticancer drug that prevents HSP110-mediated stabilization of the oncogenic protein STAT3 [175]. A recent study shows that HSPH2, a human HSP110 homologue, is essential for the cellular role of the HSP70 HSPA1A [182].…”

Section: Regulation Of Chaperone Activitymentioning

confidence: 99%

See 1 more Smart Citation

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

et al. 2020

View full text Add to dashboard Cite

Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together to facilitate degradation of misfolded and toxic protein species through the 26S proteasome. However, the underlying mechanisms are complex and remain partly unclear. Here, we provide an overview of the current knowledge on the co-chaperones that directly take part in targeting and delivery of PQC substrates for degradation. While J-domain proteins (JDPs) target substrates for the heat shock protein 70 (HSP70) chaperones, nucleotide-exchange factors (NEFs) deliver HSP70-bound substrates to the proteasome. So far, three NEFs have been established in proteasomal delivery: HSP110 and the ubiquitin-like (UBL) domain proteins BAG-1 and BAG-6, the latter acting as a chaperone itself and carrying its substrates directly to the proteasome. A better understanding of the individual delivery pathways will improve our ability to regulate the triage, and thus regulate the fate of aberrant proteins involved in cell stress and disease, examples of which are given throughout the review.

show abstract

Section: Regulation Of Chaperone Activitymentioning

confidence: 99%

Section: Regulation Of Chaperone Activitymentioning

confidence: 99%

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Although targeting Hsp110 to stabilize ASPA C152W resulted in the accumulation of insoluble protein, it might still be a relevant target for other ASPA variants that are at least partially soluble unlike C152W. Accordingly, Hsp110 should be explored further as a potential therapeutic target to decrease the degradation of ASPA and other misfolded proteins, possibly using a recently developed inhibitor of Hsp110 (Gozzi et al, 2019), to potentially avoid or diminish the development of Canavan disease and other protein misfolding disorders.…”

Section: Discussionmentioning

confidence: 99%

Evolutionarily conserved chaperone-mediated proteasomal degradation of a disease-linked aspartoacylase variant

Gersing

Wang

Grønbæk-Thygesen

et al. 2020

Preprint

View full text Add to dashboard Cite

Canavan disease is a severe progressive neurodegenerative disorder that is characterized by swelling and spongy degeneration of brain white matter. The disease is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene, including the substitution C152W. ASPA C152W is associated with greatly reduced protein levels in cells, yet biophysical experiments suggest a wild-type like thermal stability. Here, we examine the stability and degradation pathway of ASPA C152W. When we expressed ASPA C152W in Saccharomyces cerevisiae, we found a decreased steady state compared to wild-type ASPA as a result of increased proteasomal degradation. However, molecular dynamics simulations of ASPA C152W did not substantially deviate from wild-type ASPA, indicating that the native state is structurally preserved. Instead, we suggest that the C152W substitution prevents ASPA from reaching its stable native conformation, presumably by impacting on de novo folding. Systematic mapping of the protein quality control components acting on misfolded and aggregation-prone species of C152W, revealed that the degradation is highly dependent on the molecular chaperone Hsp70, its co-chaperone Hsp110 as well as several quality control E3 ubiquitin-protein ligases, including Ubr1. In human cells, ASPA C152W displayed increased proteasomal turnover that was similarly dependent on Hsp70 and Hsp110. We propose that Hsp110 is a potential therapeutic target for misfolding ASPA variants that trigger Canavan disease due to excessive degradation.

show abstract

“…Significantly, the proposed role of HSPH1 in stress defense and its selective upregulation in diverse cancers nominate it as an attractive target for therapeutic intervention. Indeed, first attempts at targeting HSPH1 suggest this as a promising avenue for future research (Gozzi et al, 2020).…”

Section: Implications For Cancermentioning

confidence: 99%

Dual cooperation between HSP70 and the 26S proteasome in co-translational protein quality control

Tian

Chen

Yang

et al. 2020

Preprint

View full text Add to dashboard Cite

Co-translational degradation via the ubiquitin-proteasome system mediates quality control of 15 to 25% of nascent proteins, a proportion that is known to increase dramatically as a result of proteotoxic stress. Whereas the ubiquitylation machinery involved has been characterized, mechanisms coordinating the proteasomal destruction of ribosome-attached nascent proteins remain poorly defined. In pursuit of such mechanisms, we discovered dual cooperation of the HSP70 family member HSPA1 with the 26S proteasome: First, in response to proteotoxic stress, HSPA1 promotes proteasome recruitment to translating 80S ribosomes in a manner independent of nascent chain ubiquitylation. Secondly, HSPA1, in association with its cognate nucleotide exchange factor HSPH1, maintains co-translationally ubiquitylated proteins in a soluble state required for efficient proteasomal degradation. Both mechanisms conspire to confer thermotolerance to cells and to promote the growth of esophageal cancer cells in vitro and in animals. Consistent with these observations, HSPH1 knockout impedes tumor growth in vitro and in animals and correlates with favorable prognosis in digestive tract cancers, thus nominating HSPH1 as a cancer drug target.

show abstract

Selecting the first chemical molecule inhibitor of HSP110 for colorectal cancer therapy

Cited by 44 publications

References 48 publications

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

Evolutionarily conserved chaperone-mediated proteasomal degradation of a disease-linked aspartoacylase variant

Dual cooperation between HSP70 and the 26S proteasome in co-translational protein quality control

Contact Info

Product

Resources

About