Role of Key Inflammatory Protein Delineated

Researchers have identified a protein that detects and binds to cytoplasmic double-stranded DNA, thereby functioning as both a detector of infection and as a tumor suppressor.

The protein under investigation is known as AIM2 (absent in melanoma 2). It is an inflammasome, part of a multi-protein complex consisting of an assortment of proteases and signaling proteins. The exact composition of an inflammasome depends on the activator that initiates inflammasome assembly (i.e., dsDNA will trigger one inflammasome composition whereas asbestos will promote the assembly of a different variant). Inflammasomes promote the maturation of the inflammatory cytokines interleukin 1-beta and interleukin-18. In addition, inflammasomes are responsible for activation of inflammatory processes, and have been shown to induce cell pyroptosis, a process of programmed cell death distinct from apoptosis.

Investigators at Thomas Jefferson University (Philadelphia, PA, USA) sought to determine the exact role of AIM2 in the inflammatory process. They reported in the January 21, 2009, online edition of the journal Nature that their research showed that AIM2 sensed cytoplasmic DNA by means of its oligonucleotide/oligosaccharide-binding domain and interacted with ASC (apoptosis-associated speck-like protein containing a CARD) through its pyrin domain to activate caspase-1. The interaction of AIM2 with ASC also led to the formation of the ASC pyroptosome, which induces pyroptotic cell death in cells containing caspase-1. Inactivation of the AIM2 gene by short interfering RNA reduced inflammasome/pyroptosome activation by cytoplasmic DNA in human and mouse macrophages.

"Researchers have long sought this elusive protein that senses the presence of DNA in the cytoplasm, which is associated with pathogenic infection or the escape of undigested self-DNA into the cytoplasm," explained senior author Dr. Emad Alnemri, professor of biochemistry and molecular biology at Thomas Jefferson University. "We not only identified the key protein in this process, but also discovered how this protein reacts to DNA and causes inflammation. The inflammatory response triggered when AIM2 binds to foreign DNA in the cytoplasm is the body's way of alerting other systems that there is a danger present in the cell."

"The discovery and understanding of the AIM2 inflammasome should enable scientists to design novel therapeutics that modulate its activity," said Dr. Alnemri. "Such therapeutics may be useful for the treatment of nucleic acid-dependent pathogenic and autoimmune diseases, such as arthritis and systemic lupus erythematosus."

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