... understanding life in molecular detail

Dr Patricija van Oosten-Hawle

Proteostasis, Transcellular stress signalling, Protein conformational diseases, C. elegans


To maintain a healthy proteome and protect against the detrimental consquences of stress and aging, every cell has evolved ancient protein quality control mechanisms. While these mechanisms were thought to be regulated in a strict cell autonomous manner, recent advances using multicellular model organisms have shown that local proteotoxic stress is recognized and signalled to other distal tissues by transcellular stress signaling to achieve systemic proteostasis. Our research aims to uncover how a local imbalance of proteostasis is recognized and transmitted across tissue borders by secreted transcellular signalling factors. To address this, we employ genetic screens, tissue-specific next generation sequencing techniques in combination with high resolution imaging, utilizing C.elegans, as a well-established multicellular model organism.

Current major projects include:
  • Characterization of transcellular signalling factors
  • Role of transcellular stress signalling for disease intervention
  • Tissue-specific and transcellular gene regulatory networks
  • Genetic tissue-specific modification techniques in C.elegans

In all biological systems, cells throughout their lifetime are exposed to different physiological and environmental stress conditions that lead to protein damage and cellular dysfunction – and ultimately disease.

Therefore, maintaining a healthy cellular proteome is crucial to cellular health-span and viability. For example, changing environmental conditions, such as increased temperature (heat shock) pose a risk to protein folding that can cause irreversible protein damage. To protect from the detrimental consequence, cells utilize quality control mechanisms that sense and respond to misfolded proteins, such as the heat shock response that increases the expression of cytoprotective heat shock proteins (Figure 1). 

Figure 1

Figure 1: Stress conditions increase the expression of chaperones. C. elegans exposed to heat stress respond by increasing the expression of cytoprotective heat shock proteins (hsp) or chaperones, such as Hsp70 and Hsp16.  We utilize heat shock protein reporters (e.g. hsp70::RFP and hsp16::GFP as shown in this Figure) to assess the activation of this stress response in individual tissues.

Cumulative protein misfolding and aggregation is one of the hallmarks implicated in the pathologies of misfolding diseases associated with neurodegeneration, including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Parkinson’s disease, as well as cancer, diabetes and several myopathies. However, phenotypes and cellular damage associated with misfolded proteins are rarely confined to a single tissue, butoften involve peripheral tissues in ways we are only beginning to understand. Not only is there no available cure for any of these diseases; we currently also have only fragmentary insight on the molecular mechanisms of disease progression in an intact multicellular organism, as the majority of our knowledge is based on research in isolated cells in culture. Because the regulation of stress response mechanisms that maintain cellular proteostasis have been historically investigated in isolated tissue culture cells and unicellular organisms, regulation of proteostasis is understood in a strict cell-autonomous manner, regardless of the health state of neighbouring cells. However recent evidence in different multicellular model systems, such as fruit fly D. melanogaster and nematode C. elegans as well as mammalian tissue culture has shown that cellular stress responses are organized coordinately between and across tissues by transcellular chaperone signalling in metazoans. For example an imbalance of proteostasis within one tissue is sensed and signalled to other tissues within the organism to adjust chaperone levels, minimize the risk of proteotoxic damage and increase survival. This form of integrated stress signalling functions between cells and tissues within an animal to accommodate a dynamic proteome throughout lifespan and in response to diverse stress conditions, ageing and protein misfolding diseases (Figure 2). 

Figure 2Figure 2:  Transcellular stress signalling. Tissue-specific stress can be caused by the expression of a disease-associated protein or altered ectopic expression of an essential chaperone, such as shown here for hsp90. Reduced expression of hsp90 in the intestine (through the use of tissue-specific hairpin RNAi constructs) leads to the activation of stress responses in the sender tissue (intestine) and different receiving tissues (muscle).

Despite accumulating evidence for this phenomenon, the mechanistic basis of how an imbalance of proteostasis is sensed and transmitted from a sender to a receiving tissue as well as the identity of signalling molecules that mediate transcellular responses between tissues are largely unknown.

The overall aim of our research is to determine how different tissues in a multicellular organism communicate local protein misfolding stress conditions and how it can be utilized to enhance protein quality control mechanisms in a cell non-autonomous manner. We use C. elegans, a well-established metazoan model organism for protein misfolding diseases and proteostasis. By applying techniques of genetics combined with next generation sequencing and high resolution cell imaging to study whole animal proteostasis, we intend to characterize signalling molecules that respond to proteotoxic stress in the sender cell, transmit the information to receiving cells as well as establish which transcriptional responses that enhance proteostasis are induced in the receiving tissues. 

 

Detailed research programme                  Close ▲
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Lecturer in Molecular and Cell Biology
Msc (Vienna), PhD (Amsterdam).

Postdoctoral fellow (Northwestern University, USA) 2008-2014.
PhD (Vrije Universiteit Amsterdam) 2003-2008.

Garstang Building 8.53c
School of Molecular and Cellular Biology
011334 30090
p.vanoosten-hawle@leeds.ac.uk

http://www.fbs.leeds.ac.uk/staff/profile.php?un=fbspv

Selected Publications

  1. van Oosten-Hawle, P., Porter, R.S., and Morimoto, R.I.  Regulation of organismal proteostasis by transcellular chaperone signalling. Cell 153, 1366-1378.

  2. van Oosten-Hawle, P., and Morimoto, R.I. Organismal Proteostasis: Role of cell nonautonomous regulation and intertissue stress signalling. Genes & Development, 2014 Jul 15; 28(14):1533-1543.

  3. Hawle, P., Siepmann, M., Harst, A., Siderius, M., Reusch, H. P. and Obermann, W. M. The middle domain of Hsp90 acts as a discriminator between different types of client proteins. Mol. Cell. Biol. 26, 8385-8395

  4. Hawle, P., Horst, D., Bebelman, J. P., Yang, X. X., Siderius, M. and van der Vies, S. M. Cdc37p is required for stress-induced HOG- and PKC MAPK pathway functionality by interaction with Hog1p and Slt2p (Mpk1p). Eukaryotic Cell 6, 521-532