Mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to increased Alzheimer's disease (AD) risk. Neurobiological functions of TREM2 and its pathophysiological ligands remain elusive. Here we found that TREM2 directly binds to β-amyloid (Aβ) oligomers with nanomolar affinity, whereas AD-associated TREM2 mutations reduce Aβ binding. TREM2 deficiency impairs Aβ degradation in primary microglial culture and mouse brain. Aβ-induced microglial depolarization, K inward current induction, cytokine expression and secretion, migration, proliferation, apoptosis, and morphological changes are dependent on TREM2. In addition, TREM2 interaction with its signaling adaptor DAP12 is enhanced by Aβ, regulating downstream phosphorylation of SYK and GSK3β. Our data demonstrate TREM2 as a microglial Aβ receptor transducing physiological and AD-related pathological effects associated with Aβ.

Previous studies defined a DNA element necessary for glucocorticoid repression of the pro‐opiomelanocortin (POMC) gene. The glucocorticoid receptor (GR) binds this negative glucocorticoid response element (nGRE) with an in vitro affinity similar to that of GR for positive GREs. However, whereas GR binds GREs as homodimers, a novel GR complex which forms with nGRE appears to contain three GR molecules. Biochemical characterization of this complex as well as equilibrium binding studies suggest that it is formed by sequential binding of a GR homodimer followed by binding of a GR monomer on the opposite side of the double helix. The DNA‐binding domain (DBD) of GR is sufficient for differential binding of GRE and nGRE, as bacterially‐expressed DBD formed unique nGRE complexes that contain three GR polypeptides. Thus, the POMC nGRE provides the first example of an interaction between GR and DNA in which GR binds otherwise than as a homodimer. Despite its high affinity for GR, the nGRE differs significantly from GREs in that it does not activate transcription in any context. As the nGRE appears insufficient on its own to confer hormone responsiveness, other POMC promoter elements are likely to be required to mediate glucocorticoid repression.

Background: Parkin is recruited to defective mitochondria to promote degradation by an autophagy mechanism (mitophagy). Results: VDACs specifically interact with Parkin on defective mitochondria and are required for efficient targeting of Parkin to mitochondria and subsequent mitophagy. Conclusion: VDACs recruit Parkin to defective mitochondria. Significance: A novel mechanistic aspect of Parkin-dependent mitophagy is proposed that may be relevant to Parkinson disease.

The mechanisms of regulation, activation and signal transduction of the angiotensin II (Ang II) type 1 (AT1) receptor have been studied extensively in the decade after its cloning. The AT1 receptor is a major component of the renin-angiotensin system (RAS). It mediates the classical biological actions of Ang II. Among the structures required for regulation and activation of the receptor, its carboxyl-terminal region plays crucial roles in receptor internalization, desensitization and phosphorylation. The mechanisms involved in heterotrimeric G-protein coupling to the receptor, activation of the downstream signaling pathway by G proteins and the Ang II signal transduction pathways leading to specific cellular responses are discussed. In addition, recent work on the identification and characterization of novel proteins associated with carboxyl-terminus of the AT1 receptor is presented. These novel proteins will advance our understanding of how the receptor is internalized and recycled as they provide molecular mechanisms for the activation and regulation of G-protein-coupled receptors.

Temporal and tissue-specific alterations in gene expression have profound effects on aging of multicellular organisms. However, much remains unknown about the patterns of molecular changes in different tissues and how different tissues interact with each other during aging. Previous genomic studies on invertebrate aging mostly utilized the whole body or body parts and limited age-points, and failed to address tissue-specific aging. Here we measured genome-wide expression profiles of aging in Drosophila melanogaster for seven tissues representing nervous, muscular, digestive, renal, reproductive, and storage systems at six adult ages. In each tissue, we identified hundreds of age-related genes exhibiting significant changes of transcript levels with age. The age-related genes showed clear tissue-specific patterns: <10% of them in each tissue were in common with any other tissue; <20% of the biological processes enriched with the age-related genes were in common between any two tissues. A significant portion of the age-related genes were those involved in physiological functions regulated by the corresponding tissue. Nevertheless, we identified some overlaps of the age-related functional groups among tissues, suggesting certain common molecular mechanisms that regulate aging in different tissues. This study is one of the first that defined global, temporal, and spatial changes associated with aging from multiple tissues at multiple ages, showing that different tissues age in different patterns in an organism. The spatial and temporal transcriptome data presented in this study provide a basis and a valuable resource for further genetic and genomic investigation of tissue-specific regulation of aging.

Ferroptosis, an iron-dependent non-apoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here we reported that the RNA binding protein RBMS1 participated in lung cancer development through mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 was a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3¢-and 5¢-UTRs of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake and promotes ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis.Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potentials and clinical values.

The glucocorticoid receptor (GR) is a hormone-inducible transcription factor which activates transcription of specific genes by binding to a DNA sequence present in the promoters of inducible genes. These glucocorticoid response elements (GREs) have a conserved palindromic sequence. Each half-GRE palindrome binds one subunit of GR. We have assessed the relative affinity of GR monomers and homodimers for GRE and determined whether homodimer formation is rate-limiting for high affinity GRE binding. The in vitro affinity of GRE binding by GR homodimers was approximately 2 x 10(-10) M, whereas it was approximately 1 nM for GR monomers. While homodimer:GRE complexes were very stable, monomer:GRE complexes appeared less stable in vitro. At low receptor concentration, GR preferentially bound GRE as a homodimer. Prior dilution of GR (equilibrium shifted to monomers) before addition to a GRE binding reaction resulted in slower kinetics of binding by comparison to parallel reactions in which concentrated (largely homodimeric) GR was added first. Taken together, these experiments suggest that homodimer formation is rate-limiting for high affinity GRE binding. A GRE mutant which contained only a half-binding site and which was unable to bind GR homodimers was also unable to confer glucocorticoid-inducible transcription. Taken together with previous work, these experiments support the model that GR homodimers are required for hormone-dependent activation of transcription and that receptor homodimer formation is rate-limiting for GRE binding.

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