Cellular homeostasis relies on having dedicated and coordinated responses to a variety of stresses. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a common stress that triggers a conserved pathway called the unfolded protein response (UPR) that mitigates damage, and dysregulation of UPR underlies several debilitating diseases. Here, we discover that a previously uncharacterized 54-amino acid microprotein PIGBOS regulates UPR. PIGBOS localizes to the mitochondrial outer membrane where it interacts with the ER protein CLCC1 at ER–mitochondria contact sites. Functional studies reveal that the loss of PIGBOS leads to heightened UPR and increased cell death. The characterization of PIGBOS reveals an undiscovered role for a mitochondrial protein, in this case a microprotein, in the regulation of UPR originating in the ER. This study demonstrates microproteins to be an unappreciated class of genes that are critical for inter-organelle communication, homeostasis, and cell survival.

Edited by Dennis R. VoelkerFatty acid esters of hydroxy fatty acids (FAHFAs) are a recently discovered class of biologically active lipids. Here we identify the linoleic acid ester of 13-hydroxy linoleic acid (13-LAHLA) as an anti-inflammatory lipid. An oat oil fraction and FAHFA-enriched extract from this fraction showed anti-inflammatory activity in a lipopolysaccharide-induced cytokine secretion assay. Structural studies identified three LAHLA isomers (15-, 13-, and 9-LAHLA) as being the most abundant FAHFAs in the oat oil fraction. Of these LAHLAs, 13-LAHLA is the most abundant LAHLA isomer in human serum after ingestion of liposomes made of fractionated oat oil, and it is also the most abundant endogenous LAHLA in mouse and human adipose tissue. As a result, we chemically synthesized 13-LAHLA for biological assays. 13-LAHLA suppresses lipopolysaccharide-stimulated secretion of cytokines and expression of pro-inflammatory genes. These studies identify LAHLAs as an evolutionarily conserved lipid with anti-inflammatory activity in mammalian cells.Fatty acid esters of hydroxy fatty acids (FAHFAs) 4 are a recently discovered class of lipids with anti-diabetic and anti-inflammatory activity (1). Because there are numerous FAHFAs, they are classified into families based on the composition of fatty acid and hydroxy fatty acid. For example, palmitic acid esters of hydroxy stearic acids (PAHSAs) and oleic acid esters of hydroxy stearic acids (OAHSAs) are two FAHFA families. Furthermore, within a FAHFA family, there are multiple regioisomers that differ in the position of the ester linkage (e.g. 5-PAHSA and 9-PAHSA) (1).Biological testing of 5-and 9-PAHSA revealed potent antidiabetic and anti-inflammatory activity (1-3). Mechanistic studies revealed that FAHFAs regulate several cellular and physiological pathways, with at least some of the biology being attributable to agonism of GPR120 and GPR40, two G proteincoupled receptors (1, 3). Other ligands for these G proteincoupled receptors include saturated and polyunsaturated fatty acids (4, 5). GPR120 is the endogenous receptor for omega-3 fatty acids, and it mediates the anti-inflammatory effects of these lipids (5).The anti-inflammatory activity of FAHFAs has been reported in vitro and in vivo (1, 2). Initially, cellular experiments with bone marrow-derived dendritic cells showed that treatment of cells with 9-PAHSA reduced the amplitude of cytokine secretion and expression of cellular inflammation markers. In addition, administration of 9-PAHSA to mice on a high-fat diet reduced inflammation in adipose tissue of treated mice (1). 9-PAHSA also showed robust anti-inflammatory activity in a mouse colitis model. Administration of 9-PAHSA to mice undergoing chemically induced colitis improved clinical and molecular inflammation (2). Moreover, an analysis of the impact of 9-PAHSA on the immune system revealed effects on the innate and adaptive immune system (2). Most recently, Kuda et al. (6) demonstrated that docosahexaenoic acid of 13-hydroxy linoleic acid (13-DHAHLA), a...

The human ␦ epithelial sodium channel (␦ENaC) subunit is related to the ␣-, ␤-, and ␥ENaC subunits that control salt homeostasis. ␦ENaC forms an amiloride-sensitive Na ؉ channel with the ␤ and ␥ subunits. However, the in vivo function of ␦ENaC is not known. To gain insight into the function of ␦ENaC, a yeast two-hybrid screen of a human brain cDNA library was carried out using the C-and N-terminal domains of ␦ENaC. A novel ␦ENaC-interacting protein called Murr1 (mouse U2af1-rs1 region) was isolated in the C-terminal domain screen. Murr1 is a 21-kDa protein mutated in Bedlington terriers suffering from copper toxicosis. The interaction of Murr1 and ␦ENaC was confirmed by glutathione Stransferase pulldown assay and coimmunoprecipitation. To test the functional significance of the interaction, Murr1 was coexpressed with ␦␤␥ENaC in Xenopus oocytes. Murr1 inhibited amiloride-sensitive sodium current in a dose-dependent manner. In addition, deletion of the last 59 amino acids of ␦ENaC abolished the inhibition. Murr1 also bound to the ␤-and ␥ENaC subunits and inhibited ␣␤␥ENaC sodium current. Therefore, these results suggest that Murr1 is a novel regulator of ENaC.

We longitudinally imaged the developing dendrites of adult-born mouse dentate granule cells (DGCs) in vivo and found that they underwent over-branching and pruning. Exposure to an enriched environment (EE) and constraining dendritic growth by disrupting Wnt signaling led to increased branch addition and accelerated growth, which were, however, counteracted by earlier and more extensive pruning. Our results indicate that pruning is regulated in a homeostatic fashion to oppose excessive branching and promote a similar dendrite structure in DGCs.

When Pichia pastoris adapts from methanol to glucose growth, peroxisomes are rapidly sequestered and degraded within the vacuole by micropexophagy. During micropexophagy, sequestering membranes arise from the vacuole to engulf the peroxisomes. Fusion of the sequestering membranes and incorporation of the peroxisomes into the vacuole is mediated by the micropexophagy-specific membrane apparatus (MIPA). In this study, we show the P. pastoris ortholog of Atg9, a novel membrane protein is essential for the formation of the sequestering membranes and assembly of MIPA. During methanol growth, GFP-PpAtg9 localizes to multiple structures situated near the plasma membrane referred as the peripheral compartment (Atg9-PC). On glucose-induced micropexophagy, PpAtg9 traffics from the Atg9-PC to unique perivacuolar structures (PVS) that contain PpAtg11, but lack PpAtg2 and PpAtg8. Afterward, PpAtg9 distributes to the vacuole surface and sequestering membranes. Movement of the PpAtg9 from the Atg9-PC to the PVS requires PpAtg11 and PpVps15. PpAtg2 and PpAtg7 are essential for PpAtg9 trafficking from the PVS to the vacuole and sequestering membranes, whereas trafficking of PpAtg9 proceeds independent of PpAtg1, PpAtg18, and PpVac8. In summary, our data suggest that PpAtg9 transits from the Atg9-PC to the PVS and then to the sequestering membranes that engulf the peroxisomes for degradation.