Claudio Hetz

Adjunct Professor of Immunology and Infectious Diseases

Department of Immunology and Infectious Diseases

Department of Immunology and Infectious Diseases

651 Huntington Avenue
Boston, MA 02115
Phone: 161.743.0924

Research

08/05- HARVARD SCHOOL OF PUBLIC HEALTH, BOSTON, USA. Department of Immunology and Infectious Diseases. Postdoctoral Research Fellow. Involvement of the transcriptional factor XBP-1 in neurodegenerative disorders. Advisor: Laurie H. Glimcher, M.D.

08/04-08/05 DANA-FARBER CANCER INSTITUTE, BOSTON, USA. HOWARD HUDHES MEDICAL INSTITUTE. Department of Cancer Immunology & AIDS. Postdoctoral Research Fellow. Study of new regulatory activities of the BCL-2 protein family in the endoplasmic reticulum. Advisor: Stanley Korsmeyer, M.D.

01/02-07/04 SERONO PHARMACEUTICAL RESEARCH INSTITUTE, GENEVA, SWITZERLAND. Department of Neurobiology. PhD. In Biomedical Sciences, doctoral thesis: “The role of the Unfolded Protein Response and Endoplasmic Reticulum Stress in Prion-related disorders”. Advisor: Claudio Soto, Ph.D.

03/00-12/01 UNIVERSITY OF CHILE, SANTIAGO, CHILE. Faculty of Medicine, Institute of Biomedical Sciences. Residence of Ph.D. Study of Fas signaling in lymphoid cells involved in non-apoptotic cell death. Advisor: Andrew Quest, Ph.D.

03/95-03/00 UNIVERSITY OF CHILE, SANTIAGO, CHILE. Faculty of Sciences. Degree of Molecular Biotechnology Engineer. Degree thesis: “Cytotoxic mechanism of the bacterial forming-channel Microcin E492 in human carcinoma cells”. Advisor: Rosalba Lagos, Ph.D. and Maria R. Bono, Ph.D.

 

MISSIONThis laboratory focuses on understanding the molecular basis of perturbations of subcellular organelle function, their relationship to pathological conditions affecting the nervous system, and the development of prototypic therapies to prevent this damage.
I. ORGANELLE STRESS
Alterations in organelle function have devastating consequences for the proper function of the cell. Stress injuries initiate multiple signaling responses, either to adapt to the new conditions or to activate specific apoptosis pathways, if a critical threshold of damage has been reached. Our laboratory is committed to the study of cellular strategies involved in adaptation to chronic organelle damage, which are linked to several neurological disorders. The endoplasmic reticulum (ER) has important cellular functions, highlighting its role as a sophisticated machinery for protein folding and secretion. Alterations on ER function lead to the accumulation of unfolded proteins at its lumen, a cellular condition termed “ER stress”. ER stress engages an integrated signaling pathway known as the “Unfolded Protein Response” (UPR), which aims to restore homeostasis. Sustained ER stress ultimately promotes apoptosis, where the members of the BCL-2 family of proteins are essential in the initiation of cell death. Nevertheless, the mechanisms that control the transition from an adaptive state to cell death processes remain unknown and is a central subject of our research.

 

The UPRosome
How do cells sense protein folding stress? ER stress stimulates distinct stress sensors including IRE1, PERK and ATF6. IRE1 is part of the most conserved signalling branch of the UPR and harbors kinase and endoribonuclease (RNAse) activities within its cytosolic domain. IRE1 multimerization leads to the trans-autophosphorylation of its cytosolic domain, activating the RNAse domain. Active IRE1 processes the mRNA of X-Box binding protein-1 (XBP-1), shifting its codon reading frame with resultant expression of an active transcription factor (XBP-1s). XBP-1 mediates the upregulation of crucial UPR-related genes involved in folding, secretion, ER biogenesis, protein quality control and autophagy. Although PERK and IRE1 share functionally similar ER-luminal sensing domains and both are simultaneously activated in cellular paradigms of ER stress in vitro, they are selectively engaged in vivo by the physiological stress of unfolded proteins. The differences in terms of tissue-specific regulation of the UPR may be explained by the formation of distinct regulatory protein complexes. This concept is supported by the recent identification of adaptor and modulator proteins that directly interact with IRE1. We have identified a key role of the BCL-2 and Bax Iinhibitor-1 family of proteins in the control of the kinetics of IRE1 activation and inactivation. Our results support a model where IRE1 signaling emerges as a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, a complex referred to as the UPRosome.

 

ER STRESS in PHYSIOLOGY and DISEASE
ER stress is a hallmark feature of secretory cells and many diseases including cancer, neurodegeneration, and diabetes. Our laboratory is particularly committed to neurological diseases linked to abnormal protein misfolding, including, Prion disorders, Amyotrophic lateral sclerosis (ALS), Huntington’s Disease, Parkinson’s disease, in addition to Spinal Cord Injury.

 

Our central research questions are:

 

  • What are the molecular mechanisms involved in the regulation of the UPR and its relationship with the apoptosis and autophagy machinery.
  • What is the contribution of the UPR to pathological conditions affecting the nervous system.

Education

Ph.D. in Biomedical Sciences and degree in Molecular Biotechnology Engineer