The study led by Karbstein's lab, "A Translation-Like CycleIs a Quality Control Checkpoint for Maturing 40S Ribosome Subunits," waspublished in the July 6 edition of the Elsevier journal
Cell, and shows that a "quality control" function exists forribosomal subunits that use the protein-production process called translationto do a kind of test-run, but ultimately don't produce a protein.
"What is important here is that the test cycle involves thesame translational factors that are involved in normal translation," saysKarbstein, a lead author of the study. "It's the most elegant and efficient wayto produce perfect ribosomes."
Ribosomes are the targets of many commercially usedantibiotics and represent a promising area of research because of theimportance of ribosome assembly and function for cell growth. But ribosomes mayhold the key to a much greater medical need—cancer—as there arewell-established links between defects in ribosome assembly and most forms ofthe disease.
Karbstein and her colleagues were able to show that duringtranslation, the newly made ribosome subunit initially joins with itscomplementary preexisting subunit to form a much larger complex through theinfluence of a single translation factor. This large ribosome complex containsno messenger RNA, which is blocked by assembly factors, and thus produces noprotein. Once the major functions of the smaller ribosome subunit have beeninspected and approved, another translation factor breaks up the complex, andactual protein production occurs.
"For several of the assembly factors, it has been shown thatthe presence of a molecule is required, but if you take one out, it's like adomino effect—the whole thing falls apart," explains Karbstein.
The study noted that the majority of assembly factorsinvolved in this translation-like test cycle are conserved in creatures rangingfrom one-celled organisms to humans, suggesting that this evolutionarymechanism is common to all.
"Our work has been one of the first—and definitely thecleanest—work to describe the potential quality control step. The truth is,there is no data to suggest that if you disrupt this process, there will be alack of quality control, but the pathway we uncovered has all the hallmarks toensure a quality-control system."
Having shown that parts of this translation-like cycle areused to inspect ribosomal particles before releasing them into the translationpool, Karbstein and her colleagues are now trying to uncover more informationabout the degradation pathway, with the hope of finding a way to disable it.
"Eventually, we could try to develop small molecules tomodulate this pathway to help diseases like cancer, where too many ribosomes areimplicated, and other diseases that don't have enough ribosomes, like DiamondBlackfan Anemia," says Karbstein.
The first author of the study was is Bethany S. Strunk ofScripps Research. Other authors included Megan N. Novak, an undergraduate from
Furman University who worked at Scripps as a summer intern, and Crystal L.Young, also of Scripps Research. The study was supported by the
U.S. NationalInstitutes of Health, the
National Science Foundation and the
Scripps ResearchKellogg School of Science and Technology.
