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An autophagisome consuming corrupt fat cells.

A research team at the University of New Mexico continues to unlock the body’s immune system, pinpointing a protein that directly organizes autophagy, the vital internal cell-scrubbing process that maintains the intracellular landscape by gathering and disposing of worn-out proteins and invading microorganisms.

Autophagy is the body’s early immune response to inflammation and other disease processes, regulating which cells live and die. This process acts as a defense against harmful viruses and bacteria.

UNM Professor and Chair of the Molecular Genetics and Microbiology Department Vojo Deretic, PhD, and colleagues are able to provoke an early immunity response through autophagy in the human body through the “immunity-related GTPase family M” protein, or IRGM, a distinctly human gene where mutations causing inflammatory diseases often occur. IRGM plays a direct role in organizing autophagy’s antimicrobial and anti-inflammatory functions in Crohn’s disease and other inflammation-related illnesses.

In his more than 20 years of research with the human immune system, Deretic has explored immunity regulators used to prevent excessive inflammation associated with Mycobacterium tuberculosis (TB), Crohn’s disease and Inflammatory Bowel Disease. Now his team has established that IRGM physically interacts directly with key autophagy activators and regulators like ULK1 and Beclin 1. Furthermore, IRGM interacts with pattern recognition receptors, like NOD2 and ATG16L1 – Crohn’s disease risk factors – forming a molecular complex that activates core autophagy machinery with antimicrobial and anti-inflammatory functions. “We have defined the exact molecular process that IRGM controls in responding to inflammatory diseases,” he asserts.

These new findings provide valuable insight into the molecular process that uses the human body’s built-in immune system to prevent infectious diseases, and reveal its potential to suppress inflammation associated with a host of diseases. “We expected a more indirect mechanism and process that assembled this core autophagy machinery,” Deretic admits. “But now we know that the IRGM autophagy regulator is the very centerpiece of the early immune response process in humans. Without it, we all would suffer some form of inflammatory disease.”

The dual roles of autophagy in controlling the bacterial burden and suppressing inflammation that leads to disease make the process an attractive target for development of therapeutics. “We’re exploring how to induce IRGM pharmacologically now that we know how it’s regulated and what it does,” Deretic offers. Deretic’s team is screening existing FDA-approved anti-inflammatory drugs and candidates to determine new treatments through drug repurposing.

Findings are available in the May 2015 issue of Molecular Cell. Visit http://www.sciencedirect.com/science/article/pii/S1097276515002117 to read the full paper.