Uwe Linne

A human-specific long noncoding RNA regulator of antigen-presenting cell viability and antimicrobial defense.

Macrophages are essential for both, to clear pathogens and preserve tissue homeostasis, yet the molecular regulators of this equilibrium remain incompletely defined. Here, we identify SAILR (survival associated immune-regulatory RNA), a primate-specific long noncoding RNA (lncRNA), as a critical modulator of macrophage viability under infection conditions. SAILR is induced during monocyte-to-macrophage differentiation, but rapidly downregulated upon bacterial challenge in a nuclear factor kappa B (NF-κB) dependent manner. In both naïve and immune-activated macrophages, SAILR dampens the expression of adhesion, phagocytosis, and invasion factors, which include SIGLEC1 and MMP7. During infection with Salmonella Typhimurium, depletion of SAILR sensitizes macrophages to apoptosis, resulting in loss of intracellular replication niches and reduced bacterial recovery. Conversely, enforced SAILR expression promotes macrophage survival and increases intracellular pathogen burden. Mechanistically, SAILR interacts with the antiapoptotic adaptor protein 14-3-3β to support macrophage survival. Notably, downregulation of SAILR is mirrored in circulating immune cells from patients with severe COVID-19 and sepsis. Together, our findings position SAILR as a central regulator in linking macrophage survival to host-pathogen interaction and disease pathophysiology.

Molecular insights into the promiscuous Ap4N hydrolase YqeK.

Diadenosine tetraphosphate (Ap4A) and related dinucleoside tetraphosphates (Ap4Ns) are important stress-signalling molecules that coordinate bacterial adaptation to changing environmental conditions. Although the enzymes for turnover of Ap4A are known in several bacteria, the structural basis for substrate recognition and the cellular consequences of impaired Ap4A turnover remain poorly understood. Here, we characterize the Histidine-Aspartate (HD)-domain hydrolase YqeK from Bacillus subtilis. Deletion of yqeK impaired growth in stationary-phase, sporulation, and biofilm formation demonstrating a general role upon nutrient limitation. YqeK forms a homodimer and functions as a manganese-dependent phosphohydrolase symmetrically cleaving Ap4A into two ADP molecules and removing Ap4A caps from RNA. The enzyme was active not only toward Ap4A but also toward the mixed dinucleotides Ap4G, Ap4C, and Ap4U in both in vitro and in vivo assays, hence acting as a broad-spectrum regulator of Ap4N homeostasis. To understand this promiscuity, we determined crystal structures of YqeK in its apo- and ADP-bound state and in complex with a non-hydrolysable Ap4A analogue. The structures revealed an asymmetric recognition mechanism in which one nucleoside moiety and the proximal phosphate groups are tightly coordinated, whereas the distal nucleoside is accommodated largely through nonspecific interactions, explaining the ability of YqeK to process diverse substrates. Together, our findings establish YqeK as a central regulator of dinucleotide homeostasis and RNA metabolism and provide the structural framework for Ap4N recognition by HD-domain phosphohydrolases.

Discovery of a Cell-Permeable Gi-Signaling Inhibitor