Meet Your Heat Shock Proteins

An Introduction

Like many milestone discoveries, heat shock proteins (HSPs) were discovered by accident. In 1962, the Italian scientist Ferruccio Ritossa was studying fruit fly genetics, when one morning he found his incubator to be set at a temperature higher than normal. Ritossa amusingly denied responsibility for the mistake, even in his write-up of his finding.  He says "I do not remember whether it was John Pulitzer or Inge or Clara Ghini and Giordano who shifted the temperature of my incubator, but one day I noticed a different puffing pattern!"[1] A “puffing pattern” is seen under a microscope when a gene is being transcribed. Those genes were transcribing heat shock proteins, although it would be years before we would know that, and decades before we would know the real significance of that discovery. In fact, we are still discovering the full significance of his discovery. 

Proteins 101

Before we dive in, let’s make sure we are on the same page, with a brief recap on proteins.  What exactly are proteins? Like, a side of chicken? Smaller. We are diving into the cells of that chicken—the microscopic cells that make up every tissue and organ in your body.
Our cells are crowded places. They are not the clean, spacious line drawing from your high school biology textbook, with a nucleus and mitochondrion separated by a white page, substrates moseying over in a leisurely backstroke.  Each of our cells can contain billions of proteins, doing thousands of different jobs.  That line drawing was a bit simplified, of course.  Our cells are astoundingly busy and complex micro-verses.  

Protein Folding 

There are thousands of different proteins- well over 10,000 are identified, and that number increases quickly. By different proteins, I mean different genes encoding proteins with different structures. Proteins are all made of the same 20 amino acids, in long chains of differing sequences, which then fold in into a secondary and tertiary, and sometimes a quaternary structure. [2] Just as the 26 letters in our alphabet form words and then sentences and then a nearly endless number of phrases, the 20 amino acids can form enormous numbers of different protein shapes. And, like the placement of letters and words determines meaning, so does the shape of the protein determine its function.  The enzyme must be the right shape to hold two substrates together, channels must allow a precise number of molecules to pass based on a signal, and a receptor must match its ligand exactly.  The act of proteins folding into their precise shape, and maintaining that shape, is big business in the cell, and a significant amount of the cell's resources are allocated to making sure this goes right. [3]

Housekeeping Proteins

 There are thousands of known different proteins, but only about 10% of these make up most of the proteins in our cells, under normal conditions (about 70% of the proteins in the cell)[2]. These are the regulars, sometimes called the “housekeeping proteins” because they maintain the essential functions of day to day life (metabolism, growth, movement, communication). They are the essential workers.   Heat shock proteins are key essential workers.  One could even argue they are the most essential workers.  They are one of our most abundant proteins, up to 10% of the proteins in a typical cell under normal conditions [4] (so, 10% of that 70%, or 1/7th of the essential workers).  They are also one of or the most conserved families of proteins, meaning they are in all life forms, from prokaryotic bacteria to humans, and they are very similar in all species, having changed very little since the beginning of life.  So, they must be pretty important…

Heat Shock Proteins: Guardians of Protein Shape.

Chaperones and Heat Shock Proteins

We are not quite done with protein folding. Remember the genetic code is translated into a chain of amino acids.  The chain then folds back on itself in its secondary structure, and then again into a tertiary structure, resulting in a unique and precise shape. Of note, some amino acids are hydrophobic, and prefer to be on the inside of the protein (think oily or sticky), and some are hydrophilic, and tend to be on the surface of the folded protein. Folding is such an important function that the cell has a huge family of proteins that is responsible for overseeing the process.  These are called chaperone proteins, or  molecular chaperones.Chaperone proteins and heat shock proteins were being discovered independently in the 1970s, and it was not recognized until the 1980s that there was a large overlap in the two families].  The names stuck though, which often causes confusion even today, decades later. They are sometimes used interchangeably, however technically this is not correct, as only about one fifth of chaperone proteins are activated by heat. [5]

Unfolding and Misfolding

While it is true that the shape of a protein must be precisely accurate, it also cannot be too rigid or unyielding. Many proteins must change their shape to function. Enzymes bind their substrates and catalyze a reaction and then release the product, channels open and close, myosin and actin contract and relax muscles. The protein must be flexible enough to move and function, even to change shape a little, but not so flexible that it falls apart under stress. There is a “just right” level of fluidity or flexibility.  
Yes, proteins can fall apart under stress. Heat stress is a type of stress. Protein “stress” is any factor that causes proteins to increasingly lose their shape and function, and conditions under which the cell struggles to maintain homeostasis.  This could be changes in temperature or pH, low glucose or oxygen, toxic chemicals or heavy metals, radiation, and oxidative stress (oxidative stress is now understood to perhaps be more accurately stated to be the stress rather than just one of the causes of it.)
One final thing about protein unfolding: when a protein unfolds, those “sticky” amino acids that were happily tucked away into the middle of the cell, can become exposed. When multiple proteins unfold, and start floating around bumping into each other, they can stick together via these sticky spots. If this is not controlled, they continue to form large aggregates, which are toxic to the cell. [6]

Toxic Protein Aggregates

Remember how crowded a cell can be? Imagine the cell is a busy airport. Everyone is focused on their task at hand. People swerve around and squeeze past each other, not paying much attention, just focused on where they want to go. Carts go whizzing by with the shrill beep of the horn telling pedestrians to make way. Occasionally they get slowed up a little, but normally the system functions. Now, imagine a cart loses a wheel. The axle drops, and the cart stops short. Now another cart comes along, and bumps the broken cart, and gets a flat tire, and a pole gets bent and sticks out to the side. The pole now hooks the next cart coming through, and so on and so on until there is a huge barricade of broken carts and nothing can get through. Now people start missing their flights, and the pilots can’t get past, and eventually, if not cleared, the whole airport comes to a halt.

Heat Shock Proteins: a crucial cellular defense mechanism

Heat shock proteins are the cart mechanics. They constantly survey the airport for cart breakdowns, and rush over to help as soon as they see a problem.  The goal is to fix the problem and get the cart moving again, which if caught early, is often what happens. If they can’t fix it, they at least will get it out of the way, so it doesn't cause a pile up.  And under typical conditions, they are able to do one of these things, and the airport/ cell keeps running smoothly. 

References

1. De Maio A, Santoro MG, Tanguay RM, Hightower LE. Ferruccio Ritossa’s scientific legacy 50 years after his discovery of the heat shock response: a new view of biology, a new society, and a new journal. Cell Stress Chaperones. 2012;17(2):139-143. doi:10.1007/s12192-012-0320-z 

2. Finka A, Goloubinoff P. Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis. Cell Stress Chaperones. 2013;18(5):591-605. doi:10.1007/s12192-013-0413-3 

3. Kuzu OF, Granerud LJT, Saatcioglu F. Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations. Signal Transduct Target Ther. 2025;10:358. doi:10.1038/s41392-025-02439-w 

4. Hu C, Yang J, Qi Z, et al. Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities. MedComm. 2022;3(3):e161. doi:10.1002/mco2.161 

5. Richter K, Haslbeck M, Buchner J. The Heat Shock Response: Life on the Verge of Death. Mol Cell. 2010;40(2):253-266. doi:10.1016/j.molcel.2010.10.006 

6. Early steps of protein disaggregation by Hsp70 chaperone and class B J-domain proteins are shaped by Hsp110 - PMC. Accessed September 3, 2026. https://pmc.ncbi.nlm.nih.gov/articles/PMC11479587/ 

Hyperthermia: Fever vs External Heat

The critical differences in mechanisms, and why you should not use a sauna when you have a fever 

Both fever and external heat exposure can raise your core body temperature to similar degrees. But they represent fundamentally different physiological mechanisms.  In fact, parts of the processes could be said to be opposites. Which is intriguing and curious, and also has important safety implications. 

First, what is “core temperature” and why does it matter so much?

Human core body temperature is the temperature of the vital organs within the thoracic and abdominal cavities.  It is maintained within a narrow range, approximately 36º-38ºC (96.8–100.4°F), under normal conditions. This precise control reflects the narrow range at which our cells and particularly our proteins are designed to function most efficiently. 

Core body temperature and protein shape

Proteins are the molecules in our cells that “do” everything. They carry out all our cellular processes. They catalyze reactions, control movement of fluids and nutrients, transport substrates, form the structure of the cell, and more. A protein’s shape is essential to its function. Shape must have some degree of fluidity,  as all these processes are dynamic and many require slight shifts in shape as they do their jobs.

Between 36–38°C our proteins are at the ideal flexibility to carry out their functions. But with more heat, they become unstable, and with too much heat they start to unfold and become dysfunctional. When many proteins become unfolded, they start to clump together, forming protein aggregates that are toxic to the cell. We want to avoid this.  

Thermoregulation and the thermostat in your brain

The hypothalamus is a deep brain structure just above the midbrain that is responsible for maintaining temperature homeostasis.  It receives information from temperature sensors throughout the body, like tiny thermometers set up in our core and vital organs, as well as our skin and peripheral muscles.  If temperature starts to drift from its “set point” (normally 98.6ºF), it initiates mechanisms to compensate. The body has mechanisms to dissipate heat when temperatures rise (sweating, decreased activity), and others to generate and conserve heat when our temperature drops (shivering, decreasing surface area by huddling, increasing metabolism).

Heat dissipation: how your brain cools you down

When our core temperature starts rising, or the hypothalamus determines we are under heat stress (it can learn to detect a recurring impending heat stress before our core temp rises at all), it increases blood flow to the skin, and activates eccrine sweat glands. These are our two primary mechanisms of heat dissipation, and they work together. 

Our extremities are normally several degrees cooler than is our core, and this gradient can increase depending on conditions and source of heat. Blood that flows through the skin cools, and the cooler blood is then brought back to the core. This works together with the activation of eccrine sweat glands in the skin which is our most important cooling mechanism.  Sweat evaporation can continue to cool the skin and blood even when air temperature is higher than the body. 

Fever: our thermostat Reset

when your fever is rising, your hypothalamus thinks you are hypothermic.  If the set point is 102ºF, anything below that, you will feel cold and be shivering under blankets.  And this is why when the fever “breaks,” and the set point drops back to normal, suddenly you are throwing the 10 blankets off and sweating profusely.  

Fever: The thermostat turned up

Clinically, a fever is defined as a core temperature of ≥38°C (100.4°F). With a fever, the body’s thermostat in the  hypothalamus is set higher than normal.  This is usually in response to an infection, where the immune system is active and releasing pyrogens, which cause this bump in the internal thermostat. The body actively generates heat through shivering, vasoconstriction, and behavioral responses such as huddling up to reduce surface area exposure, and seeking warmth. 

This is why, when your fever is rising, regardless of what your actual body temperature is, your hypothalamus thinks you are hypothermic.  If the set point is trying to get you to 102ºF, anything below that, 101.5ºF even, you will feel cold and be shivering under blankets.  And this is why when the fever “breaks,” and the set point drops back to normal, suddenly you are throwing the 10 blankets off and sweating profusely.  

Importantly, thermoregulatory control is preserved. Even when temperatures exceed 40°C (104°F), fever itself rarely causes direct harm because the hypothalamus continues to regulate the process.

External heating: Body temperature rises despite the thermostat’s cooling efforts

I am going to talk about hyperthermia in the context of thermal therapy, where one intentionally raises their core body temperature through modalities such as a sauna or hot tub.    During thermal therapy, core temperatures can reach 38–39°C (100.4–102.2°F). This is generally the goal. It is a slight stress on the body that results in strengthening our cellular responses, and activates heat shock proteins.  What is important, and why it very rarely results in heat illness or heat stroke, is that we remain in control, able to remove the heat source and lower our temperature when we are ready

Hyperthermia occurs when a heat source is putting heat into the body, or preventing the body from dissipating heat, and the body cannot maintain temperature homeostasis.  The body's cooling mechanisms are in full force, but they are being overwhelmed by the external heat. 

The set point of the “thermostat” that the hypothalamus is aiming for, has not changed.  It is trying to get you to 98.6ºF.  So, compared with our rising fever example where we had maximal heat production and conservation mechanisms at 101ºF, in a sauna, or with external heating, you will be sweating and feel hot.  The hypothalamus has activated maximal cooling responses: profuse sweating, cutaneous vasodilation, and increased cardiac and respiratory output.  They are not keeping up, and your body temperature is still rising, but it is important to note here that they are having an effect, and without them your body temperature would be much higher,   

Why avoid sauna use with a fever

In healthy individuals with intact thermoregulatory function, controlled heat exposure poses minimal risk, as the body’s cooling mechanisms remain active throughout the session.  While body temperature is elevated, our cooling mechanisms keep it from becoming dangerously elevated.  

Thermal therapy is not recommended during active fever, as the elevated hypothalamic set point and altered thermoregulatory responses make heat exposure unpredictable. The body is not trying to keep the body temp at our normal 98.6º.  It may be set at 104ºF, so with an added heat source, our temp would go straight there before cooling mechanisms would even start.  We don’t know where it would land. 

We do know that your thermoregulatory mechanisms are not functioning normally when you have a fever, and unlike when you are healthy, we do not know how your body will respond to the heat.  So it is safest to avoid heat therapy while sick with a febrile illness.