XBP‐1, a transcription factor that drives the unfolded protein response (UPR), is activated in B cells when they differentiate to plasma cells. Here, we show that in the B cells, whose capacity to ...secrete IgM has been eliminated, XBP‐1 is induced normally on induction of differentiation, suggesting that activation of XBP‐1 in B cells is a differentiation‐dependent event, but not the result of a UPR caused by the abundant synthesis of secreted IgM. Without XBP‐1, B cells fail to signal effectively through the B‐cell receptor. The signalling defects lead to aberrant expression of the plasma cell transcription factors IRF4 and Blimp‐1, and altered levels of activation‐induced cytidine deaminase and sphingosine‐1‐phosphate receptor. Using XBP‐1‐deficient/Blimp‐1‐GFP transgenic mice, we find that XBP‐1‐deficient B cells form antibody‐secreting plasmablasts in response to initial immunization; however, these plasmablasts respond ineffectively to CXCL12. They fail to colonize the bone marrow and do not sustain antibody production. These findings define the role of XBP‐1 in normal plasma cell development and have implications for management of B‐cell malignancies.
Transforming growth factor-β (TGF-β) family signaling pathways have roles in both neuronal development and the regulation of synaptic function. Here we identify a novel role for the Caenorhabditis ...elegans DAF-7/TGF-β signaling pathway in the regulation of the AMPA-type glutamate receptor GLR-1. We found that the abundance of GLR-1 increases at synapses in the ventral nerve cord (VNC) of animals with loss-of-function mutations in multiple DAF-7/TGF-β pathway components including the TGF-β ligand DAF-7, the type I receptor DAF-1, and the Smads DAF-8 and DAF-14. The GLR-1 defect can be rescued by expression of daf-8 specifically in glr-1-expressing interneurons. The effect on GLR-1 was specific for the DAF-7 pathway because mutations in the DBL-1/TGF-β family pathway did not increase GLR-1 levels in the VNC. Immunoblot analysis indicates that total levels of GLR-1 protein are increased in neurons of DAF-7/TGF-β pathway mutants. The increased abundance of GLR-1 in the VNC of daf-7 pathway mutants is dependent on the transcriptional regulator DAF-3/Smad suggesting that DAF-3-dependent transcription controls GLR-1 levels. Furthermore, we found that glr-1 transcription is increased in daf-7 mutants based on a glr-1 transcriptional reporter. Together these results suggest that the DAF-7/TGF-β signaling pathway functions in neurons and negatively regulates the abundance of GLR-1, in part, by controlling transcription of the receptor itself. Finally, DAF-7/TGF-β pathway mutants exhibit changes in spontaneous locomotion that are dependent on endogenous GLR-1 and consistent with increased glutamatergic signaling. These results reveal a novel mechanism by which TGF-β signaling functions in the nervous system to regulate behavior.
The Doublesex/Mab-3 Domain transcription factor DMD-10 is expressed in several cell types in
, including in the nervous system. We sought to investigate whether DMD-10 is required for normal neuronal ...function using behavioral assays. We found that mutation of
did not broadly affect behavior.
mutants were normal in several behavioral assays including a body bends assay for locomotion, egg laying, chemotaxis and response to gentle touch to the body.
mutants did have defects in nose-touch responsiveness, which requires the glutamate receptor GLR-1. However, using quantitative fluorescence microscopy to measure levels of a GLR-1::GFP fusion protein in the ventral nerve cord, we found no evidence supporting a difference in the number of GLR-1 synapses or in the amount of GLR-1 present in
mutants.
mutants did have decreased responsiveness to high osmolarity, which, along with nose-touch, is sensed by the polymodal sensory neuron ASH. Furthermore, mutation of
impaired behavioral response to optogenetic activation of ASH, suggesting that
promotes neuronal signaling in ASH downstream of sensory receptor activation. Together our results suggest that DMD-10 is important in regulating the frequency of multiple ASH-dependent behavioral responses.
Controlled localization of class II MHC molecules is essential for proper class II MHC-restricted antigen presentation and the subsequent initiation of an adaptive immune response. Ubiquitination of ...class II MHC molecules on cytosolic lysine (K225) of the β-chain has been shown to affect localization of the complex. We generated mice in which the endogenous β-chain locus is replaced with a GFP tagged mutant version that lacks the cytosolic lysine residue (I-A-β-K225R-EGFP). These mice have elevated levels of class II MHC as compared to I-A-β-EGFP mice, and immature bone marrow-derived dendritic cells show redistribution of class II MHC to the cell surface. Nonetheless, in these same cells efficiency of antigen presentation is unaffected in I-A-β-K225R-EGFP mice, as assayed for presentation of ovalbumin to appropriately specific T cells. The I-A-β-K225R-EGFP animals have normal CD4 T cell populations and are capable of generating antigen-specific antibody in response to model antigens and viral infection. We therefore conclude that in our experimental system modulation of trafficking by ubiquitination of residue K225 of the β-chain is not essential for the function of class II MHC products in antigen presentation or antibody production.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The accumulation of misfolded secreted IgM in the endoplasmic reticulum (ER) of X-box binding protein 1 (XBP-1)-deficient B cells has been held responsible for the inability of such cells to yield ...plasma cells, through the failure to mount a proper unfolded protein response. LPS-stimulated B cells incapable of secreting IgM still activate the XBP-1 axis normally, as follows: XBP-1 is turned on by cues that trigger differentiation and not in response to accumulation of unfolded IgM, but the impact of XBP-1 deficiency on glycoprotein folding and assembly has not been explored. The lack of XBP-1 compromised neither the formation of functional hen egg lysozyme-specific IgM nor the secretion of free kappa-chains. Although XBP-1 deficiency affects the synthesis of some ER chaperones, including protein disulfide isomerase, their steady state levels do not drop below the threshold required for proper assembly and maturation of the Igalpha/Igbeta heterodimer and MHC molecules. Intracellular transport and surface display of integral membrane proteins are unaffected by XBP-1 deficiency. Given the fact that we failed to observe any defects in folding of a variety of glycoproteins, we looked for other means to explain the requirement for XBP-1 in plasma cell development. We observed significantly reduced levels of phosphatidylcholine, sphingomyelin, and phosphatidylinositol in total membranes of XBP-1-deficient B cells, and reduced ER content. Terminal N-linked glycosylation of IgM and class I MHC was altered in these cells. XBP-1 hence has important roles beyond folding proteins in the ER.
Transforming growth factor-β (TGF-β) family signaling pathways have roles in both neuronal development and the regulation of synaptic function. Here we identify a novel role for the
C. elegans
...DAF-7/TGF-β signaling pathway in the regulation of the AMPA-type glutamate receptor GLR-1. We found that the abundance of GLR-1 increases at synapses in the ventral nerve cord (VNC) of animals with loss-of-function mutations in multiple DAF-7/TGF-β pathway components including the TGF-β ligand DAF-7, the type I receptor DAF-1, and the Smads DAF-8 and DAF-14. The GLR-1 defect can be rescued by expression of
daf-8
specifically in
glr-1
-expressing interneurons. The effect on GLR-1 was specific for the DAF-7 pathway because mutations in the DBL-1/TGF-β family pathway did not increase GLR-1 levels in the VNC. Immunoblot analysis indicates that total levels of GLR-1 protein are increased in neurons of DAF-7/TGF-β pathway mutants. The increased abundance of GLR-1 in the VNC of
daf-7
pathway mutants is dependent on the transcriptional regulator DAF-3/Smad suggesting that DAF-3-dependent transcription controls GLR-1 levels. Furthermore, we found that
glr-1
transcription is increased in
daf-7
mutants based on a
glr-1
transcriptional reporter. Together these results suggest that the DAF-7/TGF-β signaling pathway functions in neurons and negatively regulates the abundance of GLR-1, in part, by controlling transcription of the receptor itself. Finally, DAF-7/TGF-β pathway mutants exhibit changes in spontaneous locomotion that are dependent on endogenous GLR-1 and consistent with increased glutamatergic signaling. These results reveal a novel mechanism by which TGF-β signaling functions in the nervous system to regulate behavior.
The Nancy Grace Roman Telescope's High Latitude Wide Area Survey will have a number of synergies with the Vera Rubin Observatory's Legacy Survey of Space and Time (LSST), particularly for ...extragalactic star clusters. Understanding the nature of star clusters and star cluster systems are key topics in many areas of astronomy, chief among them stellar evolution, high energy astrophysics, galaxy assembly/dark matter, the extragalactic distance scale, and cosmology. One of the challenges will be disentangling the age/metallicity degeneracy because young (\(\sim\)Myr) metal-rich clusters have similar SEDs to old (\(\sim\)Gyr) metal-poor clusters. Rubin will provide homogeneous, \(ugrizy\) photometric coverage, and measurements in the red Roman filters will help break the age-metallicity and age-extinction degeneracies, providing the first globular cluster samples that cover wide areas while essentially free of contamination from Milky Way stars. Roman's excellent spatial resolution will also allow measurements of cluster sizes. We advocate for observations of a large sample of galaxies with a range of properties and morphologies in the Rubin/LSST footprint matching the depth of the LSST Wide-Fast-Deep field \(i\) band limit (26.3 mag), and recommend adding the F213 filter to the survey.
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