Substrate relay in an Hsp70‐cochaperone cascade safeguards tail‐anchored membrane protein targeting

Membrane proteins are aggregation‐prone in aqueous environments, and their biogenesis poses acute challenges to cellular protein homeostasis. How the chaperone network effectively protects integral membrane proteins during their post‐translational targeting is not well understood. Here, biochemical reconstitutions showed that the yeast cytosolic Hsp70 is responsible for capturing newly synthesized tail‐anchored membrane proteins (TAs) in the soluble form. Moreover, direct interaction of Hsp70 with the cochaperone Sgt2 initiates a sequential series of TA relays to the dedicated TA targeting factor Get3. In contrast to direct loading of TAs to downstream chaperones, stepwise substrate loading via Hsp70 maintains the solubility and targeting competence of TAs, ensuring their efficient delivery to the endoplasmic reticulum (ER). Inactivation of cytosolic Hsp70 severely impairs TA translocation in vivo. Our results demonstrate a new role of cytosolic Hsp70 in directly assisting the targeting of an essential class of integral membrane proteins and provide a paradigm for how “substrate funneling” through a chaperone cascade preserves the conformational quality of nascent membrane proteins during their biogenesis

Precessing Jet and Large Dust Grains in the V380 Ori NE Star-forming Region

The V380 Ori NE bipolar outflow was imaged in the SiO and CO J = 1 - 0 lines, and dense cores in L1641 were observed in the 2.0-0.89 mm continuum. The highly collimated SiO jet shows point-symmetric oscillation patterns in both position and velocity, which suggests that the jet axis is precessing and the driving source may belong to a non-coplanar binary system. By considering the position and velocity variabilities together, accurate jet parameters were derived. The protostellar system is viewed nearly edge-on, and the jet has a flow speed of 35 km/s and a precession period of 1600 years. The CO outflow length gives a dynamical timescale of 6300 years, and the protostar must be extremely young. The inferred binary separation of 6-70 au implies that this protobinary system may have been formed through the disk instability process. The continuum spectra of L1641 dense cores indicate that the emission comes from dust, and the fits with modified blackbody functions give emissivity power indices of beta = 0.3-2.2. The emissivity index shows a positive correlation with the molecular line width, but no strong correlation with bolometric luminosity or temperature. V380 Ori NE has a particularly low value of beta = 0.3, which tentatively suggests the presence of millimeter-sized dust grains. Because the dust growth takes millions of years, much longer than the protostellar age, this core may have produced large grains in the starless core stage. HH 34 MMS and HH 147 MMS also have low emissivity indices.Comment: To appear in the Astrophysical Journal Supplement Serie

Nicotinamide attenuates the decrease in dendritic spine density in hippocampal primary neurons from 5xFAD mice, an Alzheimers disease animal model

Alzheimers disease (AD) is the most common neurodegenerative disease characterized by memory loss and the presence of amyloid plaques and neurofibrillary tangles in the patients brains. In this study, we investigated the alterations in metabolite profiles of the hippocampal tissues from 6, 8, and 12 month-old wild-type (WT) and 5xfamiliar AD (5xFAD) mice, an AD mouse model harboring 5 early-onset familiar AD mutations, which shows memory loss from approximately 5 months of age, by exploiting the untargeted metabolomics profiling. We found that nicotinamide and adenosine monophosphate levels have been significantly decreased while lysophosphatidylcholine (LysoPC) (16:0), LysoPC (18:0), and lysophosphatidylethanolamine (LysoPE) (16:0) levels have been significantly increased in the hippocampi from 5xFAD mice at 8 months or 12 months of age, compared to those from age-matched wild-type mice. In the present study, we focused on the role of nicotinamide and examined if replenishment of nicotinamide exerts attenuating effects on the reduction in dendritic spine density in hippocampal primary neurons from 5xFAD mice. Treatment with nicotinamide attenuated the deficits in spine density in the hippocampal primary neurons derived from 5xFAD mice, indicating a potential role of nicotinamide in the pathogenesis of AD. Taken together, these findings suggest that the decreased hippocampal nicotinamide level could be linked with AD pathogenesis and be a useful therapeutic target for AD.This study was financially supported by the National Research Foundation of Korea (NRF) grant, funded by the Korean Government (2016R1A2B4012232) and also partly supported by Seoul National University Bundang Hospital Research Fund, South Korea (02–2013-015). HJ.K. received a scholarship from the BK21-Plus Education Program provided by the National Research Foundation of Korea