News: Multi-purpose Protein Regulates New Protein Synthesis

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Multi-purpose Protein Regulates New Protein Synthesis

Description

A signaling protein called IRE1, which helps stressed-out cells make new

proteins, may be more versatile and important than scientists believed. A

new study reveals the surprising finding that this same signaling protein is

required for the formation of immune cells.

Newswise ‹ A signaling protein called IRE1, which helps stressed-out cells

make new proteins, may be more versatile and important than scientists

believed. A new study by researchers from the University of Michigan Medical

School and the Medical Institute reveals the surprising

finding that this same signaling protein is required for the formation of

immune cells called B lymphocytes.

³This is a unique signaling pathway,² says Randal Kaufman, Ph.D., a

professor of biological chemistry in the U-M Medical School and an HHMI

investigator. ³In most pathways, there are multiple components and

crosstalk. But there¹s only one IRE1 gene and one protein that carries out a

unique biochemical reaction. This makes IRE1 a perfect target for

pharmacological intervention for B cell-driven autoimmune diseases, like

myasthenia gravis or systemic lupus erythematosus.²

Results from the study will be published in the Feb. 1 issue of the Journal

of Clinical Investigation.

Kaufman studies fundamental signaling pathways involved in the production of

new proteins in the cell¹s endoplasmic reticulum (ER). The process begins

with chains of amino acids, which are deposited in the ER membrane in

response to coded instructions from genes. Chaperone proteins fold these

amino acid chains into specific shapes and direct them to different areas of

the ER for processing.

When too many amino acids pile up in the ER membrane, or when something goes

wrong with the folding process, the entire system can get clogged with

unfolded proteins. To prevent this, the cell activates the unfolded protein

response (UPR).

³The UPR has three main aspects,² Kaufman explains. ³First, it signals the

nucleus to stop synthesizing new proteins to give the ER time to catch up.

Second, it induces expression and synthesis of more chaperone proteins to

assist with protein folding and help with protein trafficking. And third, it

activates genes involved in protein degradation to get rid of excess

unfolded proteins. So you reduce the load, get rid of garbage and increase

efficiency. If these don¹t work, the cell will die.²

³Recently, scientists have discovered that the unfolded protein response is

activated in many diseases from viral infections to stroke to Alzheimer¹s

disease,² says Kezhong Zhang, Ph.D., a senior research associate in

biological chemistry and first author of the paper. ³All these things

disrupt protein folding and put stress on the cell. By doing so, they

activate the UPR.²

Several years ago, Kaufman and his research colleagues discovered that IRE1

triggers the unfolded protein response by splicing a segment of messenger

RNA called XBP1. This leads to production of a new protein, which turns on

genes in the UPR signaling pathway and directs cells to secrete large

amounts of protein. The University of Michigan has filed a U.S. patent

application covering the IRE1-mediated processing of XBP1 mRNA.

Other scientists have shown that XBP1 helps immune cells called B

lymphocytes develop into antibody-generating plasma cells. Plasma cells

secrete large amounts of protein antibodies into the bloodstream. Antibodies

lock on to antigens ­ substances that trigger the immune response ­ until

they can be removed or destroyed by other immune cells. Knowing that XBP1

was required to create plasma cells, Zhang designed a study to see if IRE1

was involved, also.

Zhang studied mouse embryos that were missing the gene for IRE1. He found

that mice lacking both copies of IRE1 died before birth and had fewer

hematopoietic stem cells ­ precursor cells which develop into many different

types of blood and immune cells ­ than normal mice.

Zhang transplanted hematopoietic stem cells from IRE1 knock-out embryos into

mice whose bone marrow had been destroyed by radiation. He found that stem

cells deficient in IRE1 could reconstitute all types of blood and immune

cells in the transplanted mice, but their mature B lymphocytes were

defective. Without IRE1, lymphocytes don¹t develop a B cell receptor and

don¹t have the right rearrangements of immunoglobulin genes to function

properly.

³Our findings show that IRE1 is required for both the early and late stages

of B lymphocyte development, and that it works through a different mechanism

at each stage,² Zhang says.

³This is the first indication that a sensor for protein folding in the

endoplasmic reticulum can also signal the nucleus to regulate gene

rearrangements required for B cell differentiation,² Kaufman says. ³It¹s a

completely unexpected observation. Learning more about the IRE1 signaling

pathway may lead to new ways to suppress B cell development, which could be

helpful in autoimmune diseases like diabetes and lupus.²

The research was supported by the National Institutes of Health and the

Medical Institute. U-M collaborators include Hetty N. Wong and

Benbo Song, research associates; Corey N. , a U-M undergraduate

student and Donalyn Scheuner, a research specialist in the

Medical Institute.

Citation: Journal of Clinical Investigation:115 (3 ) February 1, 2005

http://www.newswise.com/articles/view/509394/