Trends in Immunology
Volume 27, Issue 2, February 2006, Pages 74-79
Journal home page for Trends in Immunology

Chaperone-related immune dysfunction: an emergent property of distorted chaperone networks

https://doi.org/10.1016/j.it.2005.11.009Get rights and content

Molecular chaperones (heat shock proteins) are important components of cellular networks, such as protein–protein and gene regulatory networks. Chaperones participate in the folding of immunologically important proteins, presentation of antigens and activation of the immune system. Here, we propose that chaperone-related immune dysfunction might be more general than was previously thought. Mutations and polymorphism of chaperones and the regulators of their synthesis, heat shock factor-1, chaperone diseases, sick chaperones and chaperone overload might all affect (mostly impairing) immune responses.

Section snippets

A central role for chaperones in networks and immune functions

Chaperones (see Glossary) are ubiquitous, highly conserved proteins, which either sequester damaged proteins, preventing their aggregation, or use a cycle of ATP-driven conformational changes to help the folding of freshly synthesized proteins and the repair of conformational protein damage. Environmental stress (a sudden change in the cellular environment, such as heat shock, to which the cell has not developed a specific adaptive response or does not have time to execute the specific adaptive

Chaperone polymorphisms and mutations

Chaperone mutations are primarily exemplified by relatively widespread chaperone single nucleotide polymorphisms, which bring a functional variability to the cross-regulated actions of the chaperone network. The 70-kDa Hsp (Hsp70) family shows exceptional polymorphism among human molecular chaperones [17]. The three major Hsp70 genes are located on chromosome 6p21 in the central part of the MHC locus, in close proximity to the genes encoding tumor necrosis factor α, lymphotoxin, complement C4

Impaired chaperone production

HSF1 is a member of a transcription factor family and is a key factor in the synthesis of most HSPs in mammals. HSF1 is activated by a sequence of events, starting from the disassembly of the HSF1–chaperone complex in the cytoplasm, through the trimerization, nuclear translocation and phosphorylation of HSF1 and ending with the binding of HSF1 to the respective DNA elements. The final transcriptional events, the dissociation of HSF1 from the DNA and its ‘recycling’ to the cytoplasm, are also

Chaperone damage and chaperone overload

Chaperones have a large hydrophobic surface to recognize damaged proteins, as well as an exceptionally high percentage of naturally disordered regions, which help them to ‘catch’ their substrates and also to undergo the conformational changes necessary for their assistance in the folding process [32]. These structural features might explain why chaperones are preferentially damaged during aging, by oxidation and other chemical modifications [30], and also show decreased activity during aging

Chaperone-related immune dysfunction

The above scenarios of impaired chaperone function (chaperone polymorphisms, chaperone mutations, impaired chaperone induction, damaged and overloaded chaperones) might all induce an immune dysfunction ranging from the invisible to the pronounced. The hypothetical pathways of chaperone-related immune dysfunction, summarized in Figure 2, are listed below:

  • (i)

    Proteasome assembly and proteasome function might become impaired, such that fewer or different antigenic peptides might be generated;

Possible therapeutic interventions

Modulation of chaperones or their induction might provide an important therapeutic platform for the development of immunomodulatory drugs. There are several examples of immunosuppressant molecules interacting with molecular chaperones. Cyclophilins and the FK506 immunosuppressant-binding proteins are target chaperones of the widely used immunosuppressants cyclosporin A and FK506, respectively. The immunosuppressant deoxyspergualine interacts with the structurally similar carboxy-terminal

Concluding remarks

Based on the available data in the literature indicating an apparent correlation of various forms of deficient chaperone function with impaired immune response (Table 1), as well as studies on the central role of chaperones in the protein interaction, signaling and transcriptional regulatory networks of the cell, we propose that chaperone mutations, chaperone polymorphisms, impaired chaperone induction, chaperone damage and chaperone overload might all contribute to various levels and forms of

Acknowledgements

E.M.V. started her research as a member of the Hungarian Research Student Association (http://www.kutdiak.hu). We acknowledge the useful comments of Lajos László and Viktor Müller, George Füst, Pramod K. Srivastava, the referees, as well as the help of Gergely Halász (Semmelweis University) in constructing Figure 1. Work in our laboratory was supported by research grants from the EU (FP6–506850, FP6–016003), Hungarian Science Foundation (OTKA-T37357, T46837 and F47281), Hungarian Ministry of

Glossary

Chaperone:
a protein (or RNA) is called a chaperone if it prevents the aggregation of other proteins, or facilitates the folding or refolding of de novo synthesized or misfolded proteins, respectively. Most (but not all) chaperones are preferentially synthesized after stress and are therefore called stress or heat-shock proteins. Chaperones are usually nonspecific; that is, they interact with various freshly synthesized or damaged proteins. However, a large number of highly specific chaperones

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