Ubiquitylation is a fundamental mechanism of signal transduction that regulates immune responses and many other biological processes. Similar to phosphorylation, ubiquitylation is a reversible process that is counter-regulated by ubiquitylating enzymes and deubiquitylating enzymes (DUBs). Despite the identification of a large number of DUBs, our knowledge of the function and activities of this family of enzymes is just starting to accumulate. As described in this Review, recent studies of several DUBs, in particular CYLD and A20, show that deubiquitylation has an important role in the regulation of both innate and adaptive immune responses.

Chlamydia trachomatis is an obligate intracellular bacterial pathogen that causes various human diseases, including blindness caused by ocular infection and sexually-transmitted diseases resulting from urogenital infection. After infecting host cells, Chlamydiae avoid alarming the host's immune system. Among the immune evasion mechanisms, Chlamydiae can inhibit NF-kappaB activation, a crucial pathway for host inflammatory responses. In this study, we show that ChlaDub1, a deubiquitinating and deneddylating protease from C. trachomatis, is expressed in infected cells. In transfection experiments, ChlaDub1 suppresses NF-kappaB activation induced by several pro-inflammatory stimuli and binds the NF-kappaB inhibitory subunit IkappaBalpha, impairing its ubiquitination and degradation. Thus, we provide further insight into the mechanism by which C. trachomatis may evade the host inflammatory response by demonstrating that ChlaDub1, a protease produced by this microorganism, is capable of inhibiting IkappaBalpha degradation and blocking NF-kappaB activation.

Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key counterregulatory roles during infection. The molecular mechanisms underlying LX-mediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2–dependent ubiquitinylation and proteasome-mediated degradation of TNF receptor–associated factor (TRAF) 2 and TRAF6, which are adaptor molecules that couple TNF and interleukin-1 receptor/Toll-like receptor family members to intracellular signaling events. LX-mediated degradation of TRAF6 inhibits proinflammatory cytokine production by dendritic cells. This restraint of innate immune signaling can be ablated by inhibition of proteasome function. In vivo, this leads to dysregulated immune responses, accompanied by increased mortality during infection. Proteasomal degradation of TRAF6 is a central mechanism underlying LX-driven immune counterregulation, and a hitherto unappreciated mechanism of action of ASA. These findings suggest a new molecular target for drug development for diseases marked by dysregulated inflammatory responses.

Machado et al. reveal a new way in which aspirin reins in inflammation—it triggers the destruction of proinflammatory signaling proteins. Aspirin’s power was initially attributed to its inhibition of proinflammatory lipids called prostaglandins—a discovery that won the Nobel Prize in 1982. Later, aspirin was also shown to beef up levels of lipids called lipoxins, which help resolve inflammation by blocking NF-κB activation and the recruitment of inflammatory cells. Lipoxins were recently found to activate SOCS2, a protein that blocks signals from growth hormone receptors by targeting downstream signaling proteins to the proteasome. To determine whether SOCS2 also blocks inflammatory signals, Machado et al. fished for its binding partners among molecules that transmit innate immune receptor signals. They now find that SOCS2 binds TRAF2 and TRAF6—adaptor proteins that are required for cytokine production by activated dendritic cells (DCs)—and seems to target them to the proteasome. Treating mice with aspirin decreased DC levels of cytokines and TRAF2 and TRAF6—effects that were mitigated by proteasome inhibitors. The same effects were not found in DCs from SOCS2-deficient mice.

Nod1 and Nod2 are intracellular proteins that are involved in host recognition of specific bacterial molecules and are genetically associated with several inflammatory diseases. Nod1 and Nod2 stimulation activates NF-kappaB through RICK, a caspase-recruitment domain-containing kinase. However, the mechanism by which RICK activates NF-kappaB in response to Nod1 and Nod2 stimulation is unknown. Here we show that RICK is conjugated with lysine-63-linked polyubiquitin chains at lysine 209 (K209) located in its kinase domain upon Nod1 or Nod2 stimulation and by induced oligomerization of RICK. Polyubiquitination of RICK at K209 was essential for RICK-mediated IKK activation and cytokine/chemokine secretion. However, RICK polyubiquitination did not require the kinase activity of RICK or alter the interaction of RICK with NEMO, a regulatory subunit of IkappaB kinase (IKK). Instead, polyubiquitination of RICK was found to mediate the recruitment of TAK1, a kinase that was found to be essential for Nod1-induced signaling. Thus, RICK polyubiquitination links TAK1 to IKK complexes, a critical step in Nod1/Nod2-mediated NF-kappaB activation.

ubiquitination important in hox inactivation, x-silencing, & cell cycle progression -- question: what is common?