Faculty of Biological Sciences

Dr Eric Hewitt

BSc, Reading; PhD, Manchester
Senior Lecturer
School of Molecular and Cellular Biology

Background: Postdoctoral work in the Department of Biochemistry, University of Dundee (1994-1996); MRC Laboratory of Molecular Cell Biology, University College London (1997-1998); Cambridge Institute for Medical Research, University of Cambridge (1999-2002). In September 2002 I was appointed as a Lecturer at the University of Leeds

Contact:  Garstang 9.58, +44(0) 113 34 33030, email address for  

You can read more about Dr Hewitt's interests here:
www.astbury.leeds.ac.uk/People/staffpage.php?StaffID=EH


Research Interests

CELL BIOLOGY OF AMYLOID DISEASE & THE IMMUNE SYSTEM

(I) Cell biology of amyloid disease

Amyloid formation is associatemacrophaged with a spectrum of human diseases, including Alzheimer’s disease, Huntington’s disease, type II diabetes and dialysis-related amyloidosis.In these diseases proteins and peptides aggregate into insoluble fibrils that accumulate in macroscopic amyloid plaques.  Amyloid deposition can result in cell death and tissue destruction, but the precise culprits and mechanisms of toxicity are poorly understood. Numerous studies suggest that oligomeric assembly intermediates are the major cytotoxic species associated with amyloid formation, which has led to the notion that amyloid fibrils are an inert end product of amyloid assembly. Our data suggest that the situation is more complex and that fibrils can also be cytotoxic, but that this is dependent on fibril length. Using β2-microglobulin, which forms amyloid in dialysis-related amyloidosis, we have shown that fragmentation of micron-length fibrils produces shorter nanoscale fibrils that resemble those formed early in amyloid assembly reactions. These nanoscale fibrils are readily internalized and sorted to lysosomes. Crucially nanoscale fibrils inhibit lysosome proteolysis and cause the missorting of lysosomal proteins. These data demonstrate that fibril length by determining the accessibility of intracellular compartments may be a key factor in amyloid disorders.  In our ongoing work we are investigating how nanoscale β2-microglobulin amyloid fibrils disrupt lysosome function and trafficking and whether other disease-associated amyloid fibrils, such as those formed in Alzheimer’s and Parkinson’s, exhibit length-dependent toxicity by disrupting the endolysosomal pathway.

Tipping KW, Karamanos TK, Jakhria T, Iadanza MG, Goodchild SC, Tuma R, Ranson NA, Hewitt EW, Radford SE. (2015). pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers. Proc Natl Acad Sci U S A 112: 5691-6.

Jakhria T, Hellewell AL, Porter MY, Jackson M, Tipping KW, Xue WF Radford SE, Hewitt EW (2014). β2-microglobulin amyloid fibrils are nanoparticles that disrupt?lysosomal membrane protein trafficking and inhibit protein degradation by lysosomes. J. Biol. Chem. 289:35781-94

Goodchild SC, Sheynis T, Thompson R, Tipping KW, Xue WF, Ranson NA, Beales PA, Hewitt EW, Radford SE. (2014) β2-Microglobulin amyloid fibril-induced membrane disruption is enhanced by endosomal lipids and acidic pH. PLoS One. 9, e104492.

Sheynis T, Friediger A, Xue WF, Hellewell AL, Tipping KW, Hewitt EW, Radford SE, Jelinek R. (2013) Aggregation modulators interfere with membrane interactions of β2-microglobulin fibrils. Biophys J. 105, 745-55

Milanesi L, Sheynis T, Xue WF, Orlova EV, Hellewell AL, Jelinek R, Hewitt EW, Radford SE, Saibil HR. (2012). Direct three-dimensional visualization of membrane disruption by amyloid fibrils. Proc Natl Acad Sci USA. 109, 20455-60.

Porter MY, Routledge KE, Radford SE, Hewitt EW (2011). Characterization of the response of primary cells relevant to dialysis-related amyloidosis to β2-microglobulin monomer and fibrils PLoS One. 6, e27353.

Woods LA, Platt GW, Hellewell AL, Hewitt EW, Homans SW, Ashcroft AE, Radford SE (2011)  Ligand binding to distinct states diverts aggregation of an amyloid-forming protein. Nat Chem Biol. 7, 730-9

Xue WF, Hellewell AL, Gosal, WS Homans, SW, Hewitt EW, Radford, SE (2009) Fibril fragmentation enhances amyloid toxicity. J. Biol Chem. 284, 34272-8

Morten, IJ, Gosal, WS, Radford, SE and Hewitt, EW. (2007) Investigation into the role of macrophages in the formation and degradation of beta-2-microglobulin amyloid fibrils. J Biol Chem. 282, 29691-700.

Borysik AJ, Morten IJ, Radford SE and Hewitt EW. (2007) Specific glycosaminoglycans promote unseeded amyloid formation from beta-2-microglobulin under physiological conditions. Kidney Int 72, 174-81.

 

 

(2) Cell biology of natural killer (NK) cells: how do NK cells kill? Natural killer cell

Natural killer (NK) cells are specialised lymphocytes that eliminate virally infected and transformed cells. NK cells play a complementary role to CTLs, as they can recognise cells that have lost expression of MHC class I molecules. NK cells store cytotoxic molecules (perforin, granzymes and Fas ligand) in their secretory lysosomes and recognition of an infected or transformed cell triggers the release of these cytotoxic molecules in order to kill the target cell. Yet, despite the pivotal role the secretory lysosome plays in NK cell function, how this organelle docks and fuses with the plasma membrane to facilitate release of cytotoxic molecules is poorly understood. We are, therefore, using a combination of cell biological and proteomic techniques with which to identify the exocytic machinery and to dissect the role that these proteins play in secretory lysosome exocytosis and target cell killing.

 

 

Hellewell AL, Foresti O, Gover N, Porter MY, Hewitt EW. (2014). Analysis of familial hemophagocytic lymphohistiocytosis type 4 (FHL-4) mutant proteins reveals that S-acylation is required for the function of syntaxin 11 in natural killer cells. PLoS One. 9, e98900.

Topham, NJ, and Hewitt, EW (2009) Natural killer cell cytotoxicity: how do they pull the trigger? Immunology. 128, 7-15.

Casey, T.M., Meade, J.L. and Hewitt, E.W. (2007). Organelle proteomics: Identification of the exocytic machinery associated with the natural killer cell secretory lysosome. Mol Cell Proteomics. 6, 767-80.

 

Faculty Research and Innovation



Studentship information

Postgraduate studentship areas:

  • Cell biology of amyloid disease
  • Cell biology of natural killer cells

See also:

Modules managed

MICR2120 - Cell Biology of Disease

Modules taught

BIOC2303 - Intermediate Biochemistry: Skills
BIOC3111/12/BIOL3112/MICR3120/BIOL5146M B - ATU - Antiviral Immunity
BIOC3160 - Laboratory/Literature/Computing Research Project
BIOC3221/22/BIOL3210 b - ATU - Folding & Diseases
BIOL2211 - Human Diseases
BIOL2301 - Intermediate Skills for Biological Sciences
BIOL2301/03/05/MICR2320 - Skills for Biol Sci, Biosciences and Microbiology
BIOL3305 - Advanced Skills in the Biosciences
BIOL3306 - Biological Sciences Research Project
BIOL3398 - Research Tools and Applications
BIOL3399 - Extended Research Project Preparation
BIOL3400 - Skills in the Cell Biology of Human Disease
BIOL5372M - Advanced Biomolecular Technologies
BIOW5901X - Foundation module
MICR1220 - Introduction to Immunology
MICR2120 - Cell Biology of Disease
MICR2120/BIOC2301 - Integrated Biochemistry/Medical Bacteriology
MICR2121 - Molecular Virology
MICR2221 - Medical Immunology
MICR2320/MICR3343 - Skills for Microbiology i
MICR3325 - Skills for Microbiologists 3
MICR3343 - Skills for Microbiology in Relation to Medicine

Committees

Member of Undergraduate School Taught Student Education Committee (Programme Manager: Microbiology)

Centre membership: The Astbury Centre for Structural Molecular Biology

Postgraduates

Chi Chau (Primary supervisor) 50% FTE
Michael Davies (Primary supervisor) 50% FTE
Atenas Posada Borbon (Primary supervisor) 50% FTE
Adrienne Seitz (Co-supervisor) 33% FTE
Lauren Yarrow (Co-supervisor) 25% FTE