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Discovering the Ubiquitin Proteolytic System

Photos by Joseph Martin/Joseph Martin Photography

“Biochemistry is the science of life. All our life processes – walking, talking, moving, feeding – are essentially chemical reactions. So biochemistry is actually the chemistry of life, and it’s supremely interesting.” -Dr. Aaron Ciechanover

At a time when the biomedical world was racing to uncover the secrets surrounding the translation of the information coded by DNA to RNA and proteins, a young Aaron Ciechanover was “falling in love with biology.”

Born to Polish immigrants, Aaron and his elder brother Joseph were encouraged to study from an early age, and it was Joseph who bought Aaron his first microscope at the age of 11.

“From early days, I remember my strong inclination towards biology, though it has taken different directions at different times,” Dr. Ciechanover said. “I remember collecting flowers on Mount Carmel and drying them in the heavy Babylonian Talmud of my brother. Then came the turtles and the lizards, and extracting chlorophyll from leaves with alcohol. I had a deep feeling that the future somehow resided in biology, in deciphering basic mechanisms, as so little was then known.”

Upon graduating high school, Aaron had to make a choice: join the Israeli Defense Force or postpone his service and obtain a university education, particularly in areas that are relevant to the military, such as medicine and different disciplines in engineering and sciences. He chose medicine in the hopes of one day becoming a practicing physician. However, after a few years of study, Dr. Ciechanover began to question his choice. After switching courses to pursue biochemistry and enrolling the help of a young Dr. Avram Hershko, who had just himself completed his post-doctoral training with Gordon Tomkins at the University of California in San Francisco (UCSF) and was recruited to establish a Unit of Biochemistry at the Technion in Haifa, Dr. Ciechanover immersed himself in the lab. It would not be until November of 1976 when Dr. Ciechanover would officially start his graduate studies with Dr. Hershko.

“At that time, his group focused mostly on studying intracellular proteolysis, and I learnt from him that he had given up on trying to identify the mediator(s) and mechanism(s) involved in serum-induced ‘pleiotropic response’. The model system that was chosen to study proteolysis was degradation of abnormal hemoglobin in the reticulocyte which is the terminally differentiating red blood cell. We were looking for a non-lysosomal and energy requiring proteolytic system and the reticulocyte no longer contains lysosomes which are removed during the final stages of its maturation before its release into the circulation.”

The researchers assumed that the same mechanism involved in differentiation and maturation of the reticulocyte is also involved in the removal of “naturally occurring” mutant abnormal hemoglobins that are synthesized in different hemoglobinopathies, such as thalassemia and sickle cell anemia, and also in the destruction of the amino acid analogs containing abnormal hemoglobins.

“We wanted to believe and hoped that this mechanism would turn out to be ‘universal’, and involved in degradation of normal proteins in all cells. Years later this assumption turned out to be correct.”

Ciechanover spent an important part of his graduate studies in the laboratory of Dr. Irwin A. Rose (Ernie), an American biochemist and collaborator of Dr. Hershko’s. In 1975, ubiquitin was discovered but no one knew what the protein did. The collaborative trio decided to uncover the mystery.

“In a breakthrough discovery, we found that the target substrate is covalently modified by multiple moieties of APF-1, a reversible modification that renders the protein substrate susceptible to degradation. This was a novel type of post-translational modification and clearly a new biological paradigm, that the elucidation of which required – as I feel today in retrospect – a different type of knowledge in biology and enzymology, and an original experimental approach. Elucidation of this modification would not have been possible without Ernie’s advice that was based on his immense knowledge in enzymology and protein chemistry, accompanied by his unbiased original thinking and approach to problem resolving. This discovery, along with the discovery in 1980 that APF-1 is ubiquitin, made Ernie and his fellows critically important partners in the historical trail of the discovery of the ubiquitin system.”

The discovery revealed that ubiquitin functions almost like a quality assurance manager. When it is time for a protein to be broken down, a ubiquitin molecule attaches itself to the protein. The tagged protein is then taken to one of many barrel-shaped chambers called proteasomes, a protein complex that digests the protein into smaller pieces. The protein fragments can be recycled and used in the construction of other substances in the cell. An understanding of this process helped researchers understand diseases, like cystic fibrosis, Parkinson’s and many types of cancer, that occur when the process goes awry.

With two fellowships (from the Leukemia Society of America and the Israel Cancer Research Fund), Dr. Ciechanover went on to carry out postgraduate studies under the supervision of Harvey Lodish at MIT. After three years, he returned to Israel to join the faculty of medicine at the Technion where he continued his research with many students, fellows and physicians, and where he is currently a Distinguished Research Professor in the Center for Vascular and Cancer Biology in the Rappaport Faculty of Medicine and Research Institute.

“I was happy to return to Israel, to my family and  friends, to a place I felt I belong. I established my own independent research group and laboratory, obtained extramural competitive funding, and continued my research on the ubiquitin system. I have been lucky to have, along the years, a group of extremely talented graduate students and post-doctoral fellows.”

In 2000, he received the Albert Lasker Award for Basic Medical Research and in 2003 the Israel Prize for Biological Research.

On January 16, 2018 Memphians woke up to a blanket of snow and ice. Even with almost a year of planning under our belts, it’s impossible to plan for everything that can go awry. As mentioned in another article, we had incorporated a visit to St. Jude Children’s Research Hospital into Dr. Ciechanover’s schedule. When we found out UTHSC was under an Administrative Closing we called on St. Jude to be our savior for Dr. Ciechanover’s scientific lecture. They, thanks to a wonderful partnership between our institutions, welcomed us with open arms.

At 3:30pm in the Marlo Thomas Center at St. Jude Dr. Ciechanover delivered a VCR Distinguished Lecture. Entitled, “The Ubiquitin Proteolytic System: From Basic Mechanisms Thru Human Diseases and on to Drug Targeting,” over 150 researchers congregated to hear from the Nobel Laureate. Dr Ciechanover’s address highlighted the timeline of discovery for the ubiquitin pathway, what we knew decades ago about the pathway to where it’s been and where we think it is going.

For those whom could not attend Dr. Ciechanover’s scientific lecture, you can watch a recording here. When prompted, please log in using your UT NetID and password to view the recording.