Sumary of Structural biology provides long-sought solution to innate immunity puzzle:
- UT Southwestern researchers report the first structural confirmation that endogenous — or self-made — molecules can set off innate immunity in mammals via a pair of immune cell proteins called the TLR4-MD-2 receptor complex.
- The work has wide-ranging implications for finding ways to treat and possibly prevent autoimmune diseases such as multiple sclerosis and antiphospholipid syndrome.
- , director of the Center for the Genetics of Host Defense (CGHD), identified lipids called sulfatides that can activate the innate immunity sensor TLR4, located on a cell’s membrane.
- “For many years, the question of whether endogenous — or self — molecules can activate innate immune receptors has been an important one,” says Beutler, a professor of immunology and internal medicine.
- This is the first study to substantiate the existence of such a TLR4 ligand, meaning a molecule that fits into the receptor, by structural studies.
- The study, which raises new and important questions, includes some observations about differences in the way the receptor responds in mice and humans.
- “Our work demonstrates that these, or perhaps other endogenous lipids, may indeed trigger activation of TLR4,” Beutler says, adding that TLR4 usually acts as a sensor of lipopolysaccharide (a lipid plus sugar molecule) — also known as endotoxin — that resides on gram-negative bacteria.
- Su adds that she and others in the Beutler lab previously reported that TLR4 and its co-receptor MD-2 can be activated by a synthetic small molecule called neoseptin-3, created in collaboration with the laboratory of Dale Boger, Ph.