New Research: No More Pain from Sunburns?

Ah, it's summer again. You're laying on your patio and fall asleep with a martini on the Ikea mini-table beside you. You doze off, dreaming about that Europe backpacking trip that you had planned with your best friend. Suddenly, you wake up and what's this? Your face hurts! Oh darn, you forgot to put on sunscreen and now your face is burning!

Many of us aren't strangers to sunburns. The characteristic red burning sensation when we've overstayed our time in the sun is a type of inflammation. Inflammation is a component of the many responses to harmful agents, including germs as well as damaged cells. Typically, the process involves the recruitment of immune cells, which destroy damaged tissue as well as germs, in an effort to promote healing. During inflammation, our pain-receptors become sensitized due to chemicals that are released from the white blood cells. Sunlight contains harmful ultraviolet B (UVB) rays, which promotes hypersensitivity to pain 24-48 hrs after exposure. In addition, UVB can cause dangerous mutations in your DNA leading to skin cancer, which is why sunscreen is very important.

John Dawes of Stephen McMahon's lab decided to study this inflammation response towards UVB. After exposing human and rat skin to UVB rays, they found both increased blood flow to the skin as well as the subject's pain thresholds dropping substantially. An analysis of genes that were turned on after UVB irradiation revealed that humans and mice share a similar response towards UVB damage. In addition, the gene that changed the most was a poorly-studied chemokine (chemicals that modulate the immune system) called CXCL5.

CXCL5 has previously been linked with certain chronic pain syndromes, so it looked like an interesting gene. They injected the CXCL5 protein directly into rat feet and saw that they were more susceptible to pain. In addition, they found that CXCL5 could attract white blood cells towards it, similar to a magnet pulling on metal. The cool thing was that blocking the action of CXCL5 raised the pain threshold after UVB treatment, so rats felt less pain in an artificial sunburn. In addition, there was less white blood cells being attracted to the site of injury.

Altogether, this study has found an interesting gene CXCL5 that is associated with the pain in sunburns. Drug companies are now considering developing a sunburn pain remedy that would contain a drug that specifically blocks CXCL5. However, one caveat is that less white blood cells will be attracted to the sunburn site, so one might get delayed healing of the damaged skin.


Dawes, J., et al. (2011) CXCL5 Mediates UVB Irradiation–Induced Pain. Science Translational Medicine 3(90):90ra60. Paper.

New Research: A Link between Cholesterol Metabolism and Lysosome Synthesis

In the immediately previous blog entry, we discussed how proteins are targeted to specific locations in the cell via zip-codes. One location is the lysosome, which functions as a recycling unit, containing enzymes that break apart portions of the cell marked for destruction. The lysosomal enzymes are brought to the lysosome using a specific zip-code, a chemical addition called mannose 6-phosphate (M6P).

One of the two proteins that adds M6P is made of two parts made from the same gene GNPTAB. Initially, a large premature protein is initially made, but it gets chopped into two pieces. Afterwards, the two products combine to form the functional M6P-adding enzyme. Patients with a disease called mucolipidosis II have mutations that prevents proper formation of the enzyme that adds M6P, leading to defective lysosomes and an inability to breakdown damaged portions of a cell. Ultimately, this leads to skeletal abnormalities and mental retardation, similar to Tays-Sachs disease which is also a disease of defective lysosomes.

Katrin Marschner of the Pohl lab wanted to find out what was the protein that caused the chopping of the premature protein. She found that a crucial part of the cleavage site was similar to the sites cut by the protein S1P. Further experiments revealed that S1P could also cleave the precursor to M6P-adding enzyme, creating a mature protein. Both mice with mutations in S1P and mice with mutations in M6P-adding enzyme had similar characteristics, such as defects in cartilage formation. Similar to when a pipe gets clogged, S1P-deficient cells had prominent accumulation of materials, further suggesting that S1P cleaves the M6P-adding enzyme.

S1P also known to be essential for regulating the body's cholesterol levels. At high levels of cholesterol, a molecular switch called SREBP gets anchored to the inside of the cell. However when cholesterol levels are low, S1P cuts off the anchor, freeing SREBP and allowing it to go to the nucleus where it turn on genes that make cholesterol.

As a result, drug companies have been investing money to find chemicals that can block S1P as a way to treat high blood cholesterol. Without S1P, SREBP cannot reach the nucleus and cholesterol is no longer made. However, this study suggests that such drugs would have the unwanted side effect of blocking proper lysosome function. This would lead to accumulation of garbage in the cell, something that is linked also to Alzheimer's and Parkinson's disease.


Marschner, K., et al (2011). A Key Enzyme in the Biogenesis of Lysosomes is a Protease that Regulates Cholesterol Metabolism. Science 33(6038):87-90. Paper

New Research: Nuclear Import of Membrane Proteins

All the cells in the body are made up of different components called organelles. For example, lysosomes recycle components of the cells, the mitochondria generate energy and the nucleus is not only stores the chemical blueprint of life (DNA), it also makes the executive decision of whether to turn genes on and off. Many of these organelles are separated from each other by barriers called membranes. Between all these organelles, proteins are being passed back and forth to different compartments through specific gates.

The nucleus has many gates called the nuclear pore complex (NPC) that regulate what can move across the nuclear membrane. Think of it as a filter; very small molecules can go through whereas large molecules normally cannot. However, the NPC has the ability to recognize a specific instruction on larger molecules called a zip-code. Think of zip-codes as a one-pass key; if a large molecule has a zip-code code for entry, it will be permitted to pass through the gate into the nucleus, but not back out unless it has the zip-code for exit.

We don't quite understand how proteins are moved across the nuclear membrane. Even more puzzling is this. The nuclear membrane actually has two-membranes bridged by the gates. There are proteins embedded in both the inner membrane and the outer membrane, yet it is not well understood how proteins are moved from the outer membrane into the inner membrane.

Anna Meinema from the Veenhoff lab explored this process for a specific inner membrane protein Heh2. She found that the transport of Heh2 into the nucleus depended on how well its zip-code could bind a protein called the karyopherin-α/β1 complex. karyopherin-α/β1 is somewhat like a parent that holds onto a kid as it crosses the street. In the nucleus, it holds onto proteins with nuclear zip-codes and carries it across the nuclear membrane.

She also found something remarkable. Proteins usually have a rigid structure, allowing them to interact with other molecules in specific orientations. However Heh2 transport depended on the presence of an unstructured region in the protein. Not only that, the unstructured region had to be of a sufficient length.

After further studies, she found how Heh2 was being transported across the nuclear membrane (see figure above). Before it crosses the membrane into the nucleus, the nuclear zip-code (NLS) gets bound to the karyopherin-α/β1 complex, which pulls the Heh2 across the nuclear membrane like a parental chaperone. However the NPC is a molecular sieve, with fibers (FG-Nups in the figure) that can block transport. To overcome this, Heh2 has unstructured regions which allows it to change shape for ease of passage through the fibers. After crossing the membrane, karyopherin-α/β1 releases the inner membrane protein Heh2.

Understanding nuclear import is important for several reasons. Firstly, the switches and signals that turn on genes often need to be transported into the nucleus. Secondly, viruses often hitchhike on the nuclear import machinery to be able to hijack the nucleus and produce hundreds of copies of itself. By studying this process, one day we may be able to design drugs to prevent entry of those signals or viruses during diseases.


Meinema, A., et al. (2011). Long Unfolded Linkers Facilitate Membrane Protein Import Through the Nuclear Pore Complex. Science 333(6038): 90-93. Paper.

New Research: Repairing the Heart with Thymosin-β4

The major cause of death in the developing world is cardiovascular disease. This is usually due to the heart's failure to meet the needs of the rest of the body, usually due to a heart attack or due to defects in heart structure. In a heart attack, coronary arteries are blocked, preventing the heart from receiving oxygen, which leads to tissue death and the associated pain. Unlike fish which can regenerate new muscle cells, humans cannot fully regenerate new heart muscle cells to replace the dead ones.

One aim of cardiac regenerative medicine is to repair the damage after a heart attack. Several strategies have been proposed. One includes taking embryonic stem cells and turning them into cardiac muscle cells; these would be grafted back into the damaged tissue to repair the heart. Another strategy is to try and inject stem cells directly into the heart from various organs. However, an ideal strategy would be a less invasive method that involves harnessing the body's own stem cells and turn them into heart cells within the patient.

The heart is surrounded by a layer called the epicardium (epi for around, cardium for heart). The epicardium plays a crucial role in heart development. Firstly, it sends instructions to the heart to program its development. In addition, the epicardium is a source of heart progenitor stem cells, which move into the heart and mature into heart muscle cells during development. One characteristic of these cells is that they have the gene Wt1 turned on. However up to now, none of these cells appeared to be detected in adults.

A recent paper by Nicola Smart from Paul Riley's group found an important breakthrough in understanding this process. For the first time, they detected cardiac progenitors within the heart. The secret was to add a a special molecule called thymosin-β4 (Tβ4), previously reported to enhance repair of the blood vessels in the heart after heart attacks. Upon addition of Tβ4 to epicardium biopsies, they could detect the presence of progenitors as well as functional heart muscle cells.

Interestingly, she was also able to detect progenitors with the Wt1 gene turned on in adults after a heart attack. They appeared about 7 days after a heart attack, and are linked with the limited cardiac regeneration seen after a heart attack. The stunning thing was an injection of Tβ4 before a heart attack caused the progenitors to appear earlier (2 days later) and at larger numbers. Not only that, these progenitors could turn into functional heart muscle cells that integrated into the damaged heart tissue. Also, the heart with Tβ4 pre-treatment worked better after a heart attack than the heart which had not received any treatment.

What does this mean? Firstly, we now know that there are cells with stem cell capabilities in the heart. Secondly, the addition of Tβ4 can enhance the regeneration abilities of the heart upon suffering a heart attack. While the study only looked at pre-treating hearts with Tβ4, it will be interesting to see if the results translate to patients who receive Tβ4 right after a heart attack. If this ends up holding true, one can see a potential therapeutic use for heart regeneration after heart attacks.


Smart, N. et al. (2011). De novo cardiomyocytes from within the activated adult heart after injury. Nature 474, 640-44. Paper