Heat shock proteins (HSPs) are a family of proteins produced by cells in response to stressful conditions, such as elevated temperatures. Found in nearly all living organisms, HSPs are deeply conserved throughout evolution. Among these, HSP70 is a particularly well-studied and widespread member. Its highly conserved structure and function underscore its significant role in maintaining cellular health.
The Cell’s Molecular Chaperone
HSP70 functions as a molecular chaperone, assisting other proteins in achieving their correct three-dimensional structures. This involves helping newly synthesized proteins fold properly as they emerge from ribosomes. It also prevents proteins from clumping into harmful aggregates, acting as a quality control mechanism within the cell.
Beyond initial folding, HSP70 can refold misfolded proteins, restoring their proper function. This chaperone activity depends on adenosine triphosphate (ATP) binding and hydrolysis, which drives cycles of substrate binding and release. HSP70 works with co-chaperones, such as J-domain proteins, to carry out these diverse functions, ensuring cellular proteins maintain their correct shapes.
HSP70 in Cellular Stress Responses
When cells encounter stressors like heat, oxidative stress, heavy metals, or inflammation, proteins can become denatured or misfolded. In response, cells significantly increase HSP70 production. This upregulation is a key part of the “heat shock response,” an adaptive mechanism that helps cells survive challenging environments.
Elevated HSP70 levels help repair damaged proteins by refolding them and clearing aggregated proteins. This protective role maintains cellular homeostasis and integrity during stress. For example, HSP70 can inhibit apoptosis, or programmed cell death, by acting on different steps of the caspase-dependent pathway, allowing cells to recover and adapt.
HSP70 and Disease Implications
HSP70’s involvement in human diseases can be both beneficial and detrimental. In neurodegenerative diseases like Alzheimer’s and Parkinson’s, HSP70 can play a protective role by helping clear toxic protein aggregates in neurons. Its ability to prevent protein misfolding and aggregation can mitigate cellular damage and improve neuronal survival. HSP70 also helps protect cells from ischemic injury, such as during a stroke, by inhibiting neuroinflammation and apoptosis.
Conversely, overexpression or dysregulation of HSP70 can contribute to disease progression, particularly in certain cancers. Many cancers show elevated HSP70 expression, promoting tumor cell proliferation and survival. HSP70’s anti-apoptotic properties can protect cancer cells from treatments designed to induce cell death, leading to therapeutic resistance. HSP70 is also implicated in some viral infections, where it can play a dual role, either interfering with viral entry or assisting viral replication. HSP70 levels can also serve as a biomarker for certain conditions, indicating their presence or severity.
Exploring HSP70 in Medical Applications
Given its multifaceted roles, HSP70 is actively investigated for its therapeutic potential in various medical applications. One strategy involves enhancing HSP70 activity using small molecules known as HSP70 inducers. These inducers could be beneficial in neurodegenerative diseases by promoting the clearance of misfolded proteins and protecting neurons from damage. Such approaches aim to support the cell’s natural protective mechanisms, potentially preventing tissue damage in conditions like ischemia.
Conversely, in cancer therapy, researchers are exploring ways to inhibit HSP70 activity. By blocking HSP70’s protective functions, cancer cells become more vulnerable to existing treatments, including chemotherapy. Several direct and indirect inhibitors of HSP70 have been developed, with some aiming to disrupt its interaction with other proteins or reduce its expression. While targeting HSP70 offers promising avenues, the complexity of its roles necessitates careful consideration to ensure specific targeting and minimize unintended side effects.