09 Mar Wistar Scientists Delineate Critical Steps in Antibody Formation
MedicalResearch.com Interview with:
Chih-Chi Andrew Hu, Ph.D.
Associate professor in Microenvironment & Metastasis Program
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: To help our body fight infections, B cells need to differentiate into plasma cells so that they can produce abundant antibodies against pathogens. Antibodies are folded and assembled in the endoplasmic reticulum (ER). Only those perfectly manufactured antibodies are allowed to be released from the ER and delivered to the outside of B cells to fight against the pathogens. IRE1 is a sensor protein that sits on the membrane of the ER, and can respond to B cell differentiation by activating the transcription factor called XBP1s. Activation of XBP1s allows B cells to expand the size of the ER and produce necessary chaperone proteins to help B cells manufacture perfect antibodies. By studying B cells that lack XBP1s, we discovered that these B cells produced dramatically increased levels of IRE1, and such IRE1 acquired phosphorylation at its serine 729 (S729).
MedicalResearch.com: What should readers take away from your report?
Response: Our studies further showed that phosphorylation of IRE1 at S729 allowed IRE1 to increase its enzymatic activity to not only produce increased levels of XBP1s but also cleave mRNAs of certain antibodies. The capability of IRE1 to cleave (and degrade) mRNAs of antibodies was termed as regulated IRE1-dependent decay or RIDD. RIDD led to dramatically decreased amounts of newly-synthesized antibody precursors that could enter the ER for folding and assembly. RIDD is clearly critical for B cells that lack XBP1s, because RIDD can prevent these cells from accumulating unfolded antibody precursors, which can lead to proteotoxicity. Very interestingly, we also discovered that a deadly toxin produced by food-poisoning Escherichia coli could rapidly and efficiently induce phosphorylation of IRE1 at S729 in B cells, leading to the ceased production of antibodies — yet another means of bacteria to evade our immune system.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: An immediately apparent project that we are working on now is to investigate phosphorylation of IRE1 at S729 in cancer cells. Only some cancer cells express IRE1 with constitutively phosphorylated S729. We are testing the potential of this phosphorylation site in conferring chemoresistance.
Chih-Hang Anthony Tang, Shiun Chang, Adrienne W. Paton, James C. Paton, Dmitry I. Gabrilovich, Hidde L. Ploegh, Juan R. Del Valle, Chih-Chi Andrew Hu. Phosphorylation of IRE1 at S729 regulates RIDD in B cells and antibody production after immunization. The Journal of Cell Biology, 2018; jcb.201709137 DOI: 10.1083/jcb.201709137
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