Biology subjects

Bhattacharya, K.

Publications and source records attributed to Bhattacharya, K..

6 recordsLinked to original sources

bioRxiv2023

Hsf1 and the molecular chaperone Hsp90 support a "rewiring stress response" leading to an adaptive cell size increase in chronic stress

Cells are exposed to a wide variety of internal and external stresses. Whereas many studies have focused on cellular responses to acute and severe stresses, little is known about how cellular systems adapt to sublethal chronic stresses. Using mammalian cells in culture, we discovered that they adapt to chronic mild stresses of up to two weeks, notably proteotoxic stresses such as heat, by increasing their size and translation, thereby scaling the amount of total protein. These adaptations render them more resilient to persistent and subsequent stresses. We demonstrate that Hsf1, well known for its role in acute stress responses, is required for the cell size increase, and that the molecular chaperone Hsp90 is essential for coupling the cell size increase to augmented translation. We term this translational reprogramming the "rewiring stress response", and propose that this protective process of chronic stress adaptation contributes to the increase in size as cells get older, and that its failure promotes aging.

cell biology↗

bioRxiv2022

Network-informed discovery of multidrug combinations for ERα+/HER2-/PI3Kα-mutant breast cancer

Breast cancer is a persistent threat to women worldwide. A large proportion of breast cancers are dependent on estrogen receptor (ER) for tumor progression. Therefore, targeting ER with antagonists, such as tamoxifen, remains standard therapy for ER+ breast cancer. The clinical benefits of monotherapy are often counterbalanced by off-target toxicity and development of resistance. Combinations of more than two drugs might be of great therapeutic value to prevent resistance, and to reduce doses, and hence, toxicity. We mined data from the literature and public repositories to construct a network of potential drug targets for synergistic multidrug combinations. With 9 drugs, we performed a phenotypic combinatorial screen with ER+ breast cancer cell lines. We identified two optimized low-dose combinations of 3 and 4 drugs of high therapeutic relevance to the frequent ER+/HER2-/PI3K- mutant subtype of breast cancer. Moreover, we validated the efficacy of the combinations in tamoxifen-resistant cell lines, patient-derived organoids, and xenograft experiments. Thus, we propose multidrug combinations that have the potential to overcome the standard issues of current monotherapies.

cancer biology↗

bioRxiv2022

Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life

The cytosolic molecular chaperone Hsp90 is essential for eukaryotic life1, 2. It is involved in multiple branches of proteostasis2, 3, and as a molecular capacitor in morphological evolution4. Although reduced Hsp90 levels cause phenotypic variations5, 6 and correlate with aging7, whether eukaryotic cells and organisms can tune the basal Hsp90 protein levels to alleviate physiologically accumulated stress is unknown. To begin to explore this question, we investigated whether and how mice adapt to the deletion of three out of four alleles encoding cytosolic Hsp90, one Hsp90{beta} allele being the only remaining one. While the vast majority of such mouse embryos die during gestation, survivors apparently manage to increase their Hsp90{beta} protein to at least wild-type levels. Further mechanistic studies revealed an internal ribosome entry site in the 5UTR of the Hsp90{beta} mRNA allowing translational reprogramming to compensate for the genetic loss of Hsp90 alleles and in response to stress. We found that the minimum amount of total Hsp90 that is required to support viability of mammalian cells and organisms is 50-70% of what is normally there. Those that fail to maintain a threshold level are subject to accelerated senescence, proteostatic collapse, and ultimately death. Therefore, considering that Hsp90 levels can be reduced [≥]100-fold in the unicellular budding yeast, critical threshold levels of Hsp90 have been markedly increased during eukaryotic evolution. The incompressible part of the steady-state levels of Hsp90 may have increased to accommodate the ever-growing complexity of the proteome8 on the path towards mammals.

molecular biology↗

bioRxiv2021

Morningness-eveningness assessment from mobile phone communication analysis

Human behaviour follows a 24-hour rhythm and is known to be governed by the individual chronotypes. Due to the widespread use of technology in our daily lives, it is possible to record the activities of individuals through their different digital traces. In the present study we utilise a large mobile phone communication dataset containing time stamps of calls and text messages to study the circadian rhythms of anonymous users in a European country. After removing the effect of the synchronization of East-West sun progression with the calling activity, we used two closely related approaches to heuristically compute the chronotypes of the individuals in the dataset, to identify them as morning persons or "larks" and evening persons or "owls". Using the computed chronotyes we showed how the chronotype is largely dependent on age with younger cohorts being more likely to be owls than older cohorts. Moreover, our analysis showed how on average females have distinctly different chronotypes from males. Younger females are more larkish than males while older females are more owlish. Finally, we also studied the period of low calling activity for each of the users which is considered as a marker of their sleep period during the night. We found that while "extreme larks" tend to sleep more than "extreme owls" on the weekends, we do not observe much variation between them on weekdays. In addition, we have observed that women tend to sleep even less than males on weekdays while there is not much difference between them on the weekends.

evolutionary biology↗

bioRxiv2019

The Hsp70/Hsp90 Co-Chaperone Hop/Stip1 Shifts the Proteostatic Balance from Folding Towards Degradation

Hop/Stip1/Sti1 is thought to be essential as a co-chaperone to facilitate substrate transfer between the Hsp70 and Hsp90 molecular chaperones. Despite this proposed key function for protein folding and maturation, it is not essential in a number of eukaryotes and bacteria lack an ortholog. We set out to identify and to characterize its eukaryote-specific function. Human cell lines and the budding yeast with deletions of the Hop/Sti1 gene display reduced proteasome activity due to inefficient capping of the core particle with regulatory particles. Unexpectedly, knock-out cells are more proficient at preventing protein aggregation and at promoting protein refolding. Without the restraint by Hop, a more efficient folding activity of the prokaryote-like Hsp70/Hsp90 complex, which can also be demonstrated in vitro, compensates for the proteasomal defect and ensures an alternate proteostatic equilibrium. Thus, cells may act on Hop to shift the proteostatic balance between folding and degradation.

cell biology↗

bioRxiv2018

The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity

The molecular chaperone Hsp90 is an essential and highly abundant central node in the interactome of eukaryotic cells. Many of its large number of client proteins are relevant to cancer. A hallmark of Hsp90-dependent proteins is that their accumulation is compromised by Hsp90 inhibitors. Combined with the anecdotal observation that cancer cells may be more sensitive to Hsp90 inhibitors, this has led to clinical trials aiming to develop Hsp90 inhibitors as anti-cancer agents. However, the sensitivity to Hsp90 inhibitors has not been studied in rigorously matched normal versus cancer cells, and despite the discovery of important regulators of Hsp90 activity and inhibitor sensitivity, it has remained unclear, why cancer cells might be more sensitive. To revisit this issue more systematically, we have generated an isogenic pair of normal and oncogenically transformed NIH-3T3 cell lines. Our proteomic analysis of the impact of three chemically different Hsp90 inhibitors shows that these affect a substantial portion of the oncogenic program and that indeed, transformed cells are hypersensitive. Targeting the oncogenic signaling pathway reverses the hypersensitivity, and so do inhibitors of DNA replication, cell growth, translation and energy metabolism. Conversely, stimulating normal cells with growth factors or challenging their proteostasis by overexpressing an aggregation-prone sensitizes them to Hsp90 inhibitors. Thus, the differential sensitivity to Hsp90 inhibitors may not stem from any particular intrinsic difference between normal and cancer cells, but rather from a shift in the balance between cellular quiescence and activity.

cancer biology↗