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Misfolded Proteins Potential Cause Rather than Consequence of Metabolic Disorders

저자:   업로드:2017-09-05  조회수:

    Protein folding is a fundamental function in the mundane operations of a cell’s daily life. Yet, when this task goes wrong, it becomes readily apparent how vital of a role 3D structure plays for the vast majority of protein molecules.


    In the past, scientists concluded that the aberrantly assembled proteins were the result of certain metabolic disorders, but new evidence from investigators at the Medical University of South Carolina (MUSC) suggests that the cell's response to unfolded or misfolded proteins could be a cause, rather than a consequence, of metabolic disorders.    


    Findings from the new study were published recently in Nature Structural & Molecular Biology in an article entitled “CNPY2 Is a Key Initiator of the PERK-CHOP Pathway of the Unfolded Protein Response.”


    "The unfolded protein response in the cell plays important roles in aging and many diseases, such as cancer, diabetes, and neurodegenerative disease," explained senior study investigator Zihai Li, M.D., Ph.D., chair of the department of microbiology and immunology at the MUSC Hollings Cancer Center. "Our study has uncovered a novel mechanism that triggers this response."


    There are links between protein-folding problems at the cellular level and a range of metabolic disorders, though it is unclear if those problems are causes or manifestations of such disorders. This study provides evidence that problems with protein folding contribute to certain metabolic disorders. When improperly folded molecules are encountered in cells, the unfolded protein response (UPR) is activated within the endoplasmic reticulum (ER). The ER is in charge of molecular quality control, making sure proteins, lipids, and other molecules are folded properly before the cell attempts to use them for metabolic processes.


    In the current study, the researchers found that the master protein called grp78 is in contact with three main signaling hubs that make up the control center of the UPR. When an unfolded, or misfolded protein is encountered by grp78, it breaks contact with those sensors and activates the UPR. The UPR then refolds or disposes of such molecules before they are shipped to the parts of the cell that need them.


    “...we report that ER luminal protein canopy homolog 2 (CNPY2) is released from grp78 upon ER stress. Free CNPY2 then engages protein kinase R-like ER kinase (PERK) to induce expression of the transcription factor C/EBP homologous protein (CHOP), thereby initiating the UPR,” the authors wrote. “Indeed, deletion of CNPY2 blocked the PERK–CHOP pathway and protected mice from UPR-induced liver damage and steatosis. Additionally, CNPY2 is transcriptionally upregulated by CHOP in a forward-feed loop to further en

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