Cyclic GMP-AMP as an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA.

The innate immune system functions as the first line of defense against invading bacteria and viruses. In this context, the cGAS/STING [cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase/STING] signaling axis perceives the nonself DNA associated with bacterial and viral infections, as well as the leakage of self DNA by cellular dysfunction and stresses, to elicit the host's immune responses. In this pathway, the noncanonical cyclic dinucleotide 2',3'-cyclic GMP-AMP (2',3'-cGAMP) functions as a second messenger for signal transduction: 2',3'-cGAMP is produced by the enzyme cGAS upon its recognition of double-stranded DNA, and then the 2',3'-cGAMP is recognized by the receptor STING to induce the phosphorylation of downstream factors, including TBK1 (TANK binding kinase 1) and IRF3 (interferon regulatory factor 3). Numerous crystal structures of the components of this cGAS/STING signaling axis have been reported and these clarify the structural basis for their signal transduction mechanisms. In this review, we summarize recent progress made in the structural dissection of this signaling pathway and indicate possible directions of forthcoming research.

Spin current driven by ultrafast magnetization of FeRh.

Laser-induced ultrafast demagnetization is an important phenomenon that probes arguably the ultimate limits of the angular momentum dynamics in solid. Unfortunately, many aspects of the dynamics remain unclear except that the demagnetization transfers the angular momentum eventually to the lattice. In particular, the role and origin of electron-carried spin currents in the demagnetization process are debated. Here we experimentally probe the spin current in the opposite phenomenon, i.e., laser-induced ultrafast magnetization of FeRh, where the laser pump pulse initiates the angular momentum build-up rather than its dissipation. Using the time-resolved magneto-optical Kerr effect, we directly measure the ultrafast-magnetization-driven spin current in a FeRh/Cu heterostructure. A strong correlation between the spin current and the magnetization dynamics of FeRh is found even though the spin filter effect is negligible in this opposite process. This result implies that the angular momentum build-up is achieved by an angular momentum transfer from the electron bath (supplier) to the magnon bath (receiver) and followed by the spatial transport of angular momentum (spin current) and dissipation of angular momentum to the phonon bath (spin relaxation).

Structural and Functional Analysis of DDX41: a bispecific immune receptor for DNA and cyclic dinucleotide.

In the innate immune system, pattern recognition receptors (PRRs) specifically recognize ligands derived from bacteria or viruses, to trigger the responsible downstream pathways. DEAD box protein 41 (DDX41) is an intracellular PRR that triggers the downstream pathway involving the adapter STING, the kinase TBK1, and the transcription factor IRF3, to activate the type I interferon response. DDX41 is unique in that it recognizes two different ligands; i.e., double-stranded DNA (dsDNA) and cyclic dinucleotides (CDN), via its DEAD domain. However, the structural basis for the ligand recognition by the DDX41 DEAD domain has remained elusive. Here, we report two crystal structures of the DDX41 DEAD domain in apo forms, at 1.5 and 2.2 Å resolutions. A comparison of the two crystal structures revealed the flexibility in the ATP binding site, suggesting its formation upon ATP binding. Structure-guided functional analyses in vitro and in vivo demonstrated the overlapped binding surface for dsDNA and CDN, which is distinct from the ATP-binding site. We propose that the structural rearrangement of the ATP binding site is crucial for the release of ADP, enabling the fast turnover of DDX41 for the dsDNA/CDN-induced STING activation pathway.