Disturbed protein homeostasis is a key event during cellular aging. Genetic mutations in proteins that increase their aggregation propensity or that impede on the protein quality control (PQC) mechanism, which maintain normal protein homeostasis, lead to accelerated aging or early onset of age-associated diseases.

Heat Shock Proteins (HSP) assist in protein folding as well as protein degradation (proteasomal and autophagosomal). The central aim of my group is to understand how the many different human HSPs are regulated to recognize their targets and steer them towards folding or degradation and how this knowledge can be exploited to combat diseases in which this protein homeostasis is disturbed.

Heat Shock Proteins (HSP) play a central role in the Protein Quality Control network that ensure proper folding and timely degradation of un- or misfolded proteins. There are several different ”HSP machines”: we focus and the different HSP70 machines that exist in cells and how they are regulated and function. Our main goals are:

  • Unravel how HSP70 are regulated to function is many different processes, from assisting in protein folding to protein degradation of many different proteins. The idea that specificity of these machines are primarily regulated by the so-called Hsp70 co-chaperones, being a large group of J-domain proteins (JDPs) and Nucleotide Exchange Factors (NEFs). We study how Hsp70 machines are regulated and also how they interact with degradation pathways like proteasomal or autophagosomal degradation.
  • Many, mostly age-related, diseases are caused by a cascade of protein aggregation (e.g. Alzheimer’s, Parkinson’s or Huntington’s disease), which indicates a failure of the PQC network to maintain protein homeostasis. We study the decline of protein homeostasis upon cellular aging and try to identify hubs in the HSP70 network that are becoming rate-limiting in and hence may be target for prevention of these protein aggregation diseases.
  • Protein aggregation diseases can also be due to mutations in HSP: so-called chaperonopathies. We study how these mutations affect HSP functions and how such may be corrected.
  • We identified one co-chaperone, called DNAJB6, that not only can delay protein aggregation cascade of several disease-causing proteins, but that itself, when mutated, caused a protein aggregation study. The physiological function of this protein (collaboration with Prof. Veenhoff, ERIBA, UMCG) in relation to its mode of action on disease-causing proteins, how it might be activated (drug screens), and how its mutation leads to disease is central research theme in my group.
  • Pathogens like virusses depend heavily on their hosts for the folding of their proteins that enables them to replicate. In collaboration with Prof. Smit (Medical Microbiology, UMCG), we study whether it is possible to inhibit specific HSP-viral protein interactions to interfere with viral replication.
  • Impairment of genomic integrity (e.g. DNA repair defects) are also associated with agre-related degeneration. Our lab showed that also this may be, at least in part, be due to disturbances in protein homeostasis. In collaboration with dr. Chen and Prof. Nollen, we now study the underlying mechanisms (in yeast) and how chaperones may actually protect from these consequences at the organismal level (c. elegans).
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Understanding how to modulate HSP function to the benefit of human health

In order for proteins to function, they require to be properly folded and timely degraded. If this fails, we refer to this as a collapse in protein homeostasis. This not only leads to a loss of function of the no longer well-folded proteins, but also to the formation of protein clumps (aggregates or amyloid) that have been shown to cause several age-related diseases. We know that Heat Shock Proteins (HSP) are important guiders (chaperones) of these folding and degradation process and mutations in HSPs may even cause such diseases. To be able to modulate HSP to the benefit of human health is of primary relevance to elucidate their mechanisms of action, understand how they are regulated and why they fail to do their job (with mutations or upon aging). With our research we aim to contribute to:

  • Fundamental biological and medical knowledge
  • Molecular causes and the pathophysiology of human diseases (mainly age-related degenerative disease)
  • Therapeutic targets and compound-based treatment strategies for human diseases
  • Biomarkers and assays to monitor failure of protein homeostasis in (aging) human cells
  • Technological innovation in life sciences and medicine

Research Interests

  • We showed extensively how DNAJB6 delays the onset of toxic aggregation in cells. Recently, we found that it plays a role in supporting protein aggregates to be fragmented in smaller pieces by the Hsp70 disaggregase and how this is required for the lysosomal degradation of the small aggregate fragments. Using mammalian cell models, we will further study the mechanistic aspects of this.

  • We discovered that a main function of DNAJB6 is to help with the assembly of nuclear pore complexes. We try to understand in detail how this works in relation to how it works in and what happens early on in degenerative disease. Hereto we use various in vitro and cellular approaches, including induced pluripotent stem cells (iPSC).

  • As we discovered that DNAJB6 is a key chaperone in the determination of the sensitivity of cells to aggregation and toxicity of several disease-causing protein, we developed a reporter assay for a medium throughput drug screen. The screen will be initated in fall 2022, and potential hit will be studied for broad validation studies.

  • DNAJB6 is part of a set of so-called non-canonical subset of DNAJB6 protein to which also DNAJB2 and DNAJB8 belong. All three proteins share functional and structural features, but also show distinctive characteristics. In this project we aim to get a better insight in their structure-function relationships.

  • We found genomic instability to lead to accumulation of protein aggregates. In this project, we now mainly use yeast to study how and if this proteomic instability has consequences for cellular ageing and what role chaperones play in that.


Small profile photo of H.H. Kampinga
Harm Kampinga Head of Department BMS, Professor of Cell Biology
Greetje Noppert Secretary - Section Molecular Cellbiology

University Medical Center Groningen (UMCG)
Department of Biomedical Sciences of Cells and Systems
Harm Kampinga - Heat shock proteins & protein homeostasis
Internal Zip code FB31
Antonius Deusinglaan 1
9700 AD Groningen 
The Netherlands

Visiting Address
University Medical Center Groningen (UMCG)
Department of Biomedical Sciences of Cells and Systems
Antonius Deusinglaan 1
Building 3215, 5th floor, room 505-A
9713 AV Groningen
The Netherlands