What viruses can teach us about the human immune system.

The first and most critical step in a host's response to viral infection is the recognition of the viral invader by the immune system.This task is carried out by a repertoire of sensor molecules, found in most organisms, that recognize features that are unique to the virus and not found in the host, such as viral double-stranded RNA.The principle that hosts are able to detect specific pathogen-derived patterns was first proposed by Charles Janeway in 1989, and since then, a number of innate immune receptors including several viral RNA and DNA sensors have been identified.These sensor proteins are part of the so-called innate immune system, the branch of the immune system that protects the host from viruses and other pathogens immediately after infection, and thus acts much earlier than the other branch of the immune system, the adaptive immune response.Following virus recognition, these sensors initiate signaling cascades that result in the induction of an antiviral program characterized by the upregulated expression of many antiviral or inflammation-inducing molecules such as cytokines like interferons.It was an exciting time in the field of innate immunity when I started my PhD studies in 2005.Two new intracellular viral RNA sensors called retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) had just been discovered.Prior to this, study of the innate immune system had focused extensively on membrane-bound receptors, such as the Toll-like receptors, which are primarily found in specialized immune cells.The discovery of RIG-I and MDA5 was exciting because these cytoplasmic sensors were found to be expressed in practically all cells in the human body, indicating that even nonimmune cells have the ability to sense viral invaders and to launch an innate immune response.We now know that RIG-I and MDA5 play a critical role in the detection of a broad range of RNA viruses, including influenza virus, dengue virus, and hepatitis C virus.When I was starting my PhD studies at Harvard University, the antiviral function of RIG-I had just been discovered, but how this sensor worked and signaled to initiate an antiviral program was unknown.Using affinity purification of the RIG-I protein and mass spectrometry analysis, I discovered that RIG-I is modified with ubiquitin molecules, a process known as ubiquitination.While most cellular proteins undergo ubiquitination, which often marks them for proteasomal degradation, I found that RIG-I was modified by a quite unique type of polyubiquitin that did not lead to proteasomal degradation of RIG-I but instead activated RIG-I to signal downstream.Another round of RIG-I purification from human cells and mass spectrometry identified the enzyme responsible for RIG-I ubiquitination and activation: tripartite motif protein 25 (TRIM25).TRIM25 belongs to the TRIM protein family of ubiquitin E3 ligases with about 70 members in humans.Our work showed for the first time that a TRIM molecule can directly activate a viral pathogen sensor through nondegradative ubiquitination and thereby promote antiviral cytokine production.Over the past several years, we have

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