Misfolded and malformed proteins are normally sequestered and modified by members of the heat shock family.  Under normal conditions, these aberrant proteins are either refolded into their proper confirmations or degraded via the ubiquitin machinery.  However, under stressed or compromised conditions, accumulations of these proteins into inclusion bodies can be a hallmark of neurodegenerative diseases (as seen in Parkinson’s disease), or exacerbate pre-existing conditions.

In a recent study, researchers at the Hebrew University of Jerusalem, in the Departments of Biological Chemistry and Genetics, have elucidated the exact roles for the well-known chaperones HSP40 and HSP70 in terms of the ubiquitin pathway for protein degradation.

By examining different conditions in terms of the co-chaperones Ssa1, Ssa2 (for HSP70) and Sis1 (for HSP40), these researchers sought to further understand the precise mechanism that underlies the ever-important ubiquitin pathway in dealing with deleterious protein aggregation associated with many neurodegenerative diseases.  In cells that were Sis1 depleted, ubiquitination was compromised, whereas cells without functional Ssa1/2, ubiquitination was still functional.  However, in cells without functional Ssa1/2, targeting these misfolded proteins for the ubiquitin pathway was seen to be diminished and led to HSP40+ inclusion body aggregation.  It seems that in this experiment, the Ssa co-chaperones were found to be dispensable but the Sis co-chaperone was indeed necessary for proper ubiquitination and subsequent degradation.

The researchers conclude that HSP40 and the Ssa1/2 co-chaperones are essential for the targeting and identification of misfolded proteins.  Also, that HSP70 and its co-chaperone Sis1 are required components for proper processing of misfolded proteins, whether they be degraded via the ubiquitin pathway or, as seen in circumstances with low HSP70 levels (as seen in ageing and certain pathologies), sequestered into an inclusion body.

The original research paper was published in: Molecular Biology of the Cell (May 2013):

Ubiquitin Conjugation Triggers Misfolded Protein Sequestration into Quality-Control Foci when HSP70 Chaperone Levels are Limiting.

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