BBB seminar: Linda M. Hendershot
Protein synthesis in the secretory pathway: life and death decisions
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Linda M. Hendershot
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Proteins destined for secretion or cell surface expression are synthesized in the endoplasmic reticulum (ER). In addition to the complexity of protein folding in any organelle, the oxidizing, calcium-rich ER environment and high concentration of unfolded proteins pose further dangers and constraints to the process. Quality control measures exist to ensure that nascent polypeptide chains are specifically prevented from traveling further along the secretory pathway until they have completed their folding or assembly. Proteins that cannot achieve a proper conformation are recognized and removed from the ER for degradation by the 26S proteasome. The same chaperones that aid protein folding are also important for targeting misfolded proteins for degradation. We have focused our studies on the ER chaperone BiP, which is the Hsp70 cognate of the mammalian ER and uses immunoglobulin heavy and light chains as substrates. BiP is required for the assembly of heteromeric Ig complexes and for the degradation of improperly folded/assembled subunits. We have begun to explore the role of various ER-localized DnaJ proteins in assisting BiP in its various functions and to characterize the pathway for the retro-translocation and degradation of defective Ig intermediates. Recent studies reveal a functional and perhaps even physical organization of resident ER proteins that could provide a means of separating these contradictory functions.
Selected publications:
Ma Y, Hendershot LM. The role of the unfolded protein response in tumour development: friend or foe? Nature Rev. Cancer 4:966-77, 2004.
Okuda-Shimizu Y, Hendershot LM. Characterization of an ERAD pathway for nonglycosylated BiP substrates, which require Herp. Mol. Cell 28:544-54, 2007.
Awad W, Estrada I, Shen Y, Hendershot LM. BiP mutants that are unable to interact with endoplasmic reticulum DnaJ proteins provide insights into interdomain interactions in BiP. Proc. Natl. Acad. Sci. USA 105:1164-9, 2008.
Host : Jaakko Saraste <jaakko.saraste@biomed.uib.no>, Department of Biomedicine