Proteins perform the vast majority of work in a cell and must maintain specific, intricate three-dimensional shapes to function correctly. A specialized family of proteins, known as heat shock proteins, acts as cellular guardians, protecting other proteins from damage and ensuring they are properly assembled. Among these guardians, Heat Shock Protein 60 (HSP60) is a prominent member of a class called chaperonins. The primary function of HSP60 is to assist in the folding of other proteins, a process fundamental to cellular health that places it at the center of cellular quality control.
The Primary Role of HSP60
The principal responsibility of HSP60 is ensuring proteins achieve their correct functional shapes, a process known as protein folding. This activity predominantly occurs within the mitochondria, where HSP60 is most abundant. It works with a partner protein, HSP10, to form a complex that provides a safe environment for newly synthesized or stress-damaged proteins to fold properly. This function is indispensable for maintaining the integrity of mitochondrial proteins, many of which help generate ATP, the cell’s main energy currency.
This chaperonin complex can be thought of as a two-chambered barrel. A newly made, unfolded protein chain enters one of the chambers, which is then capped by the HSP10 co-chaperone. Inside this isolated space, the protein has the opportunity to fold into its precise structure in a process powered by ATP.
Without this quality control, proteins could misfold and clump into toxic aggregates that disrupt normal cellular activities. The absence of functional HSP60 is lethal to cells.
Cellular Stress and HSP60 Response
While HSP60 performs its duties under normal conditions, its production significantly increases when the cell is under duress. This heightened expression is a feature of the cellular stress response. The term “heat shock protein” itself originates from the discovery that their production is ramped up at elevated temperatures. Heat can cause proteins to lose their shape, and the cell synthesizes more HSP60 to manage this damage.
The triggers for increased HSP60 production are diverse and extend beyond heat, including:
- Exposure to environmental toxins, heavy metals, and ultraviolet radiation
- Internal conditions like oxidative stress and hypoxia (oxygen deprivation)
- Infections by viruses and bacteria
The presence of pathogens leads to an increase in damaged proteins. By ramping up HSP60 production, the cell attempts to counteract the damage and maintain homeostasis.
The Dual Nature of HSP60 in Immunity
Heat Shock Protein 60 exhibits a dual role dependent on its location. Inside the cell, it is a protector that maintains protein integrity. However, when HSP60 is found outside the cell, its function changes, transforming it into an alarm signal for the immune system.
This transformation occurs when a cell undergoes severe stress or dies, releasing its contents. Extracellular HSP60 is recognized by the innate immune system as a Damage-Associated Molecular Pattern (DAMP). DAMPs are molecules released from damaged cells that signal tissue injury has occurred, triggering an inflammatory cascade to clear away the damage and initiate repair.
Immune cells, such as macrophages and dendritic cells, have receptors on their surface, including Toll-like receptors (TLRs), that bind to extracellular HSP60. This interaction activates these immune cells, causing them to release pro-inflammatory cytokines. While this inflammatory response is a necessary part of healing, a sustained presence of extracellular HSP60 can lead to chronic inflammation.
Association with Human Diseases
The complex biology of HSP60 links it to a range of human diseases, where its dual nature as both a protector and an inflammatory trigger plays a significant role. In autoimmune diseases, such as rheumatoid arthritis, HSP60 is implicated through a mechanism known as molecular mimicry. Because human HSP60 and the HSP60 produced by bacteria are structurally very similar, an immune response against a bacterial infection can become misdirected. The immune system may mistakenly attack the body’s own HSP60 on stressed cells, leading to the chronic inflammation and tissue destruction characteristic of autoimmune conditions.
HSP60 is also a contributor to cardiovascular disease, particularly atherosclerosis. Risk factors like high cholesterol and smoking can cause stress to the endothelial cells lining the artery walls. These stressed cells may then display HSP60 on their surface, where it acts as a danger signal that attracts immune cells and promotes inflammation. This chronic inflammatory process contributes to the formation of atherosclerotic plaques.
The role of HSP60 in cancer is complex. Cancer cells are under constant stress and often overexpress HSP60, which helps them survive by protecting their proteins and inhibiting programmed cell death. This protective function can make tumors more resilient to treatments like chemotherapy and radiation. Conversely, HSP60 on the surface of tumor cells can sometimes trigger an anti-tumor immune response, though this is often not enough to overcome its pro-survival roles.