Toxic and beneficial outcome of protein aggregation inside cells
With the increasing life expectancy, developing effective treatments for numerous degenerative, age-related diseases becomes of enormous medical, social and economic relevance. Hence, research on cellular and organismal aging is now the focus of several leading laboratories and has provided different hypotheses about the causes of aging. One prominent hypothesis suggests that a gradual, age-dependent decline of protein homeostasis (proteostasis) accompanied by increasing protein-aggregation is the underlying cause of many age-related loss-of-function diseases. In our lab we perform systemic analysis of protein-aggregation in age-related proteostasis stress models. We are interested to identify the response of the cellular proteome against the newly triggered aggregates due to various stresses. Simultaneously, we investigate how components of the proteostasis network, including molecular chaperones, degradation machinery and others collaborate to maintain the integrity of the proteome in the face of protein-aggregation stresses. The specific questions include:
We use modern cell biology and state-of-the-art proteomics arsenal to address our questions.
Increased supraorganization of respiratory complexes is a dynamic multistep remodelling in response to proteostasis stress. Rawat S, Ghosh S, Mondal D, Anusha V, Raychaudhuri S. J Cell Sci. 2020;133(18):jcs248492. doi: 10.1242/jcs.248492.
Read the interview of the first author, Shivali Rawat here
Aggregation of Respiratory Complex Subunits Marks the Onset of Proteotoxicity in Proteasome Inhibited Cells. Rawat S, Anusha V, Jha M, Sreedurgalakshmi K, Raychaudhuri S. J Mol Biol. 2019 431(5):996-1015.
Interplay of Acetyltransferase EP300 and the Proteasome System in Regulating Heat Shock Transcription Factor 1. Raychaudhuri S, Loew C, Koerner R, Pinkert S, Theis M, Hayer-Hartl M, Buchholz F, Hartl FU. Cell. 2014 Feb 27;156(5):975-85.
Firefly luciferase mutants as sensors of proteome stress.Gupta R, Kasturi P, Bracher A, Loew C, Zheng M, Villella A, Garza D, Hartl FU, Raychaudhuri S.Nature Methods. 2011 Sep 4; 8(10):879-84.
HYPK, a Huntingtin interacting protein, reduces aggregates and apoptosis induced by N-terminal Huntingtin with 40 glutamines in Neuro2a cells and exhibits chaperone-like activity.Raychaudhuri S, Sinha M, Mukhopadhyay D, Bhattacharyya NP. Hum Mol Genet. 2008 Jan 15;17(2):240-55.
For more details please visit group's home page: http://e-portal.ccmb.res.in/e-space/swasti/index.htm
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|Increased supraorganization of respiratory complexes is a dynamic multistep remodelling in response to proteostasis stress.||J Cell Science||2020|
|Aggregation of Respiratory Complex Subunits Marks the Onset of Proteotoxicity in Proteasome Inhibited Cells||J Mol Biol||2019|
|Cytoplasmic sequestration of the RhoA effector mDiaphanous1 by Prohibitin2 promotes muscle differentiation.||Scientific Reports||2019|
|Identification of a splice variant of optineurin which is defective in autophagy and phosphorylation||Biochim Biophys Acta Mol Cell Res.||2018|
|Interplay of Acetyltransferase EP300 and the Proteasome System in Regulating Heat Shock Transcription Factor 1||Cell||2014|
|Conserved C-terminal nascent peptide binding domain of HYPK facilitates its chaperone-like activity||Journal of Biosciences||2014|
|Firefly luciferase mutants as sensors of proteome stress||Nature Methods||2011|
|Protein Folding in the Cytoplasm and the Heat Shock Response||Cold Spring Harb Perspect Biol||2010|
|Identification of HYPK interacting proteins reveals involvement of HYPK in regulating cell growth, cell cycle, unfolded protein response and cell death||PLoS One||2009|
|HYPK, a Huntingtin interacting protein, reduces aggregates and apoptosis induced by N-terminal Huntingtin with 40 glutamines in Neuro2a cells and exhibits chaperone-like activity||Hum Mol Genet||2008|
|Huntingtin interacting protein HYPK is intrinsically unstructured||Proteins||2008|
|Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human beta-defensin 1 (HBD-1) expression in the intestinal epithelial cells||Cell Microbiol||2008|
|Increased caspase-2, calpain activations and decreased mitochondrial complex II activity in cells expressing exogenous huntingtin exon 1 containing CAG repeat in the pathogenic range||Cell Mol Neurobiol||2007|