Friday, February 27, 2009
In times of starvation, cells tighten their belts: they start to digest their own proteins and cellular organs. The process—known as autophagy—takes place in special organelles called autophagosomes. It is a strategy that simple yeast cells have developed as a means of survival when times get tough, and in the course of evolution, it has become a kind of self-cleaning process. In mammalian cells, autophagosomes are also responsible for getting rid of misfolded proteins, damaged organelles or disease-causing bacteria.
If this process malfunctions, it can result in infectious diseases, as well as cancer, Parkinson's or Alzheimer's disease. Biochemists at Frankfurt's Goethe University, working together with scientists from the University of Tromsø in Norway, the Weizmann Institute in Israel and the Tokyo Metropolitan Institute in Japan have just come up with an explanation as to how autophagosomes know exactly which proteins and organelles they should degrade.
"Although autophagy has been known for more than 30 years, it is astonishing that no-one thought of looking for the receptors that make this process so selective" explains Prof. Ivan Dikic from the Institute of Biochemistry II and the Cluster of Excellence 'Macromolecular Complexes' in Frankfurt. He had a head start in this field, since over several years, he and his group have researched and now published their work on another self-cleaning process in the cell: the degradation of small proteins in the proteasome, which acts as a kind of molecular shredder.
"We know that the molecules which are destined to be discarded are marked with the small protein ubiquitin and this is recognised by a receptor located at the gateway to the proteasome. It was natural to suggest a similar recognition mechanism for protein degradation by autophagosomes", says Dikic.
Unlike the proteasome, which is a complex molecular machine, autophagosomes simply consist of a double membrane that floats around in the cytoplasm. Not unlike white blood cells, they can engulf larger proteins or even whole cell organelles. But since they have no enzymes with which they can digest their own cargo, they fuse with lysosomes. When a Yoshinori Ohsumi's group in Japan reported that they had discovered ubiquitin-like proteins (ATG8) on the outer surface of the autophagosome and gone on to prove that they were specific for autophagy, Dikic and his colleague Dr. Vladimir Kirkin immediately began their search for potential autophagy receptors that might bind to the family of ATG8 proteins.
The team of international scientists report in the current issue of the renowned journal "Molecular Cell", that by employing methods from cell biology, biochemistry and mouse genetics, they have been able to identify a further protein, in addition to the known p62/SQSTM1 protein, that may act as a receptor. This is the protein NBR1, which has long been associated with cancer. Both proteins have a similar chain-like structure. At one end they bind to the ubiquitin that marks the protein aggregates and organelles that are to be degraded. Next to the ubiquitin-binding site is a domain that binds to the ATG8 proteins found at the autophagosomal membrane. Here, the protein waste can dock onto the autophagosome and can then be wrapped up in the membrane.
Vladimir Kirkin, who is now at Merck Serono in Darmstadt, is continuing these investigations with the long-term aim of developing new drugs. Dikic and his group are now concentrating on mitochondria - which are implicated in oxidative stress in cells - hoping to locate the receptors for autophagy on these important organelles.
http://www.cell.com/molecular-cell/abstract/S1097-2765(09)00064-1http://www.biochem2.de SOURCE:
Goethe University Frankfurt
Einstein scientists receive $10 million NIH grantFour Albert Einstein College of Medicine faculty members were awarded a five-year, $10-million grant from the National Institutes of Health to study autophagy–a fundamental cell process that may hold the key to aging.
Autophagy (which literally means "self-eating") refers to several surveillance systems that all cells rely on to find, digest, and recycle molecules within them that have become damaged. This cellular recycling both "cleans up" the cell and provides it with energy, since digested products can be used as fuel. Many studies have documented that autophagy becomes less efficient with age, allowing protein and other cellular components to gradually accumulate inside cells and, almost certainly, interfere with normal cell function.
The Einstein consortium is led by Ana Maria Cuervo, M.D., Ph.D., associate professor of developmental & molecular biology, of anatomy & structural biology, and of medicine at Einstein and one of the world's leading experts on autophagy. With the help of the NIH grant, Dr. Cuervo and her colleagues will test their hypothesis that impaired autophagy may explain the decline in organ function, weakened immunity, and other functional losses associated with aging. More specifically, the researchers will:
look at the role of two different types of autophagy in liver and brain function as well as immunity, under normal and stressful conditions analyze how these two types of autophagy change as the liver, brain, and immune system age determine how changes in autophagy that occur with age contribute to the aging of the entire organism, to the gradual deterioration of cognitive function, to the failure with age of two essential immune functions (antigen processing and presentation, and T helper cell activation and tolerance), and to abnormalities in lipid metabolism
"These studies will involve the cooperation of all four of us on the Einstein faculty who have jointly received this NIH grant," says Dr. Cuervo. The other three members of the Einstein consortium are Laura Santambrogio, M.D., Ph.D., associate professor of pathology; Fernando Macian-Juan, M.D., Ph.D., assistant professor of pathology; and Mark J. Czaja, M.D., professor of medicine.
"We're hopeful that this research project will lead to fundamental insights that will help us understand, treat or even prevent the metabolic alterations and decline in cognitive and immune function that affect us as we age," says Dr. Cuervo. "Strategies that can keep our cells' autophagic pathways operating efficiently as we get older could help us to enjoy healthier lives well into old age."
The Einstein researchers have set up a website that describes their research effort in more detail. The URL is
http://www.aecom.yu.edu/cuervo/_private/defaultPPG.htm.
SOURCE:
Albert Einstein College of Medicine