Features | Partner Sites | Information | LinkXpress
Sign In
GLOBETECH PUBLISHING LLC
GLOBETECH PUBLISHING LLC
PZ HTL SA

Tumors Benefit from Molecular Switch That Blocks T-cell Interferon Production

By BiotechDaily International staff writers
Posted on 26 Jun 2013
A molecular switch causes immune system T-cells to convert from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, a change that inhibits the production of the inflammatory cytokine interferon gamma.

The move from OXPHOS to aerobic glycolysis is a hallmark of T-cell activation and was thought to be required to meet the metabolic demands of proliferation. However, why proliferating cells would adopt this less efficient way to produce energy, especially in an oxygen-rich environment, has been a mystery.

Investigators at the Washington University School of Medicine (St. Louis, MO, USA) studied the role of the known molecular switch GAPDH glyceraldehyde 3-phosphate dehydrogenase) in the conversion of T-cells from OXPHOS to aerobic glycolysis.

GAPDH is an enzyme of approximately 37 kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules. As its name indicates, GAPDH catalyzes the conversion of glyceraldehyde 3-phosphate to D-glycerate 1,3-bisphosphate. This conversion occurs in the cytosol of the cell in two coupled steps. The first is favorable and allows the second unfavorable step to occur. In addition to this long established metabolic function, GAPDH has recently been implicated in several nonmetabolic processes, including transcription activation, initiation of apoptosis, and ER to Golgi vesicle shuttling.

The investigators reported in the June 6, 2013, issue of the journal Cell that aerobic glycolysis was specifically required for effector function in T-cells but that this pathway was not necessary for proliferation or survival. When activated T-cells were provided with co-stimulation and growth factors but were blocked from engaging glycolysis, their ability to produce interferon gamma was markedly compromised. This defect was translational and was regulated by the binding of GAPDH to interferon gamma mRNA.

"The proteins involved in glycolysis do not just disappear when glycolysis is turned off—they are pretty stable proteins, so they can hang around in the cell and participate in other processes," said senior author Dr. Erika Pearce, assistant professor of pathology and immunology at the Washington University School of Medicine. "In T-cells this can be a problem since one of these proteins, GAPDH, can inhibit the production of interferon gamma. It is like an on-off switch, and all we need to do to flip it is change the availability of sugar. T-cells often can go everywhere—tumors, inflammation, infections—but sometimes they do not do anything. If we can confirm that this same switch is involved in these failures in the body, we might be able to find a way to put the fight back into those T-cells."

"T-cells can get into tumors, but unfortunately they are often ineffective at killing the cancer cells," said Dr. Pearce. "Lack of the ability to make interferon gamma could be one reason why they fail to kill tumors. By understanding more about how sugar metabolism affects interferon production, we may be able to develop treatments that fight tumors by enhancing T-cell function."

Related Links:
Washington University School of Medicine



comments powered by Disqus

Channels

Drug Discovery

view channel
Image: Disruption and removal of malaria parasites by the experimental drug (+)-SJ733 (Photo courtesy of the University of California, San Francisco).

Experimental Antimalaria Drug Induces the Immune System to Destroy Infected Red Blood Cells

An experimental drug for the treatment of malaria was found to induce morphological changes in infected erythrocytes that enabled the immune system to recognize and eliminate them. Investigators at... Read more

Biochemistry

view channel

Blocking Enzyme Switch Turns Off Tumor Growth in T-Cell Acute Lymphoblastic Leukemia

Researchers recently reported that blocking the action of an enzyme “switch” needed to activate tumor growth is emerging as a practical strategy for treating T-cell acute lymphoblastic leukemia. An estimated 25% of the 500 US adolescents and young adults diagnosed yearly with this aggressive disease fail to respond to... Read more

Business

view channel

R&D Partnership Initiated to Reduce Development Time for New Drugs

nanoPET Pharma, GmbH (Berlin, Germany) signed an open-ended framework contract with the international pharmaceutical company Boehringer Ingelheim (Ridgefield, CT, USA). By developing customized contrast agents for research in both basic and preclinical studies, nanoPET Pharma will contribute to the enhancement of Boehringer... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.