371 research outputs found
Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity
During macroautophagy, conjugation of ATG12 to ATG5 is essential for LC3 lipidation and autophagosome formation. Additionally, ATG12 has ATG5-independent functions in diverse processes including mitochondrial fusion and mitochondrial-dependent apoptosis. In this study, we investigated the regulation of free ATG12. In stark contrast to the stable ATG12–ATG5 conjugate, we find that free ATG12 is highly unstable and rapidly degraded in a proteasome-dependent manner. Surprisingly, ATG12, itself a ubiquitin-like protein, is directly ubiquitinated and this promotes its proteasomal degradation. As a functional consequence of its turnover, accumulation of free ATG12 contributes to proteasome inhibitor-mediated apoptosis, a finding that may be clinically important given the use of proteasome inhibitors as anticancer agents. Collectively, our results reveal a novel interconnection between autophagy, proteasome activity, and cell death mediated by the ubiquitin-like properties of ATG12
RIPK3 restricts viral pathogenesis via cell death-independent neuroinflammation
Receptor-interacting protein kinase-3 (RIPK3) is an activator of necroptotic cell death, but recent work has implicated additional roles for RIPK3 in inflammatory signaling independent of cell death. However, while necroptosis has been shown to contribute to antiviral immunity, death-independent roles for RIPK3 in host defense have not been demonstrated. Using a mouse model of West Nile virus (WNV) encephalitis, we show that RIPK3 restricts WNV pathogenesis independently of cell death. Ripk3(-/-) mice exhibited enhanced mortality compared to wild-type (WT) controls, while mice lacking the necroptotic effector MLKL, or both MLKL and caspase-8, were unaffected. The enhanced susceptibility of Ripk3(-/-) mice arose from suppressed neuronal chemokine expression and decreased central nervous system (CNS) recruitment of T lymphocytes and inflammatory myeloid cells, while peripheral immunity remained intact. These data identify pleiotropic functions for RIPK3 in the restriction of viral pathogenesis and implicate RIPK3 as a key coordinator of immune responses within the CNS
Ubiquitin-dependent Degradation of p73 Is Inhibited by PML
p73 has been identified recently as a structural and functional homologue of the tumor suppressor p53. Here, we report that p73 stability is directly regulated by the ubiquitin–proteasome pathway. Furthermore, we show that the promyelocytic leukemia (PML) protein modulates p73 half-life by inhibiting its degradation in a PML–nuclear body (NB)–dependent manner. p38 mitogen-activated protein kinase–mediated phosphorylation of p73 is required for p73 recruitment into the PML-NB and subsequent PML-dependent p73 stabilization. We find that p300-mediated acetylation of p73 protects it against ubiquitinylation and that PML regulates p73 stability by positively modulating its acetylation levels. As a result, PML potentiates p73 transcriptional and proapoptotic activities that are markedly impaired in Pml−/− primary cells. Our findings demonstrate that PML plays a crucial role in modulating p73 function, thus providing further insights on the molecular network for tumor suppression
Thomason cohomology of categories
We introduce cohomology and homology theories for small categories with
general coefficient systems from simplex categories first studied by Thomason.
These theories generalize at once Baues-Wirsching cohomology and homology and
other more classical theories. We analyze naturality and functoriality
properties of these theories and construct associated spectral sequences for
functors between small categories.Comment: 22 pages. arXiv admin note: text overlap with arXiv:1112.399
Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency
Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies
Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein.
Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies
KELT-8b: A highly inflated transiting hot Jupiter and a new technique for extracting high-precision radial velocities from noisy spectra
We announce the discovery of a highly inflated transiting hot Jupiter
discovered by the KELT-North survey. A global analysis including constraints
from isochrones indicates that the V = 10.8 host star (HD 343246) is a mildly
evolved, G dwarf with K, , , an inferred mass
M, and radius
R. The planetary companion has mass , radius
, surface gravity , and density
g cm. The planet is on a roughly
circular orbit with semimajor axis AU and
eccentricity . The best-fit linear ephemeris is
BJD and
days. This planet is one of the most inflated of all known transiting
exoplanets, making it one of the few members of a class of extremely low
density, highly-irradiated gas giants. The low stellar and large
implied radius are supported by stellar density constraints from follow-up
light curves, plus an evolutionary and space motion analysis. We also develop a
new technique to extract high precision radial velocities from noisy spectra
that reduces the observing time needed to confirm transiting planet candidates.
This planet boasts deep transits of a bright star, a large inferred atmospheric
scale height, and a high equilibrium temperature of
K, assuming zero albedo and perfect heat redistribution, making it one of the
best targets for future atmospheric characterization studies.Comment: Submitted to ApJ, feedback is welcom
KELT-7b: A hot Jupiter transiting a bright V=8.54 rapidly rotating F-star
We report the discovery of KELT-7b, a transiting hot Jupiter with a mass of
MJ, radius of RJ, and an orbital
period of days. The bright host star (HD33643;
KELT-7) is an F-star with , Teff K, [Fe/H]
, and . It has a mass of
Msun, a radius of Rsun, and
is the fifth most massive, fifth hottest, and the ninth brightest star known to
host a transiting planet. It is also the brightest star around which KELT has
discovered a transiting planet. Thus, KELT-7b is an ideal target for detailed
characterization given its relatively low surface gravity, high equilibrium
temperature, and bright host star. The rapid rotation of the star (
km/s) results in a Rossiter-McLaughlin effect with an unusually large amplitude
of several hundred m/s. We find that the orbit normal of the planet is likely
to be well-aligned with the stellar spin axis, with a projected spin-orbit
alignment of degrees. This is currently the second most
rapidly rotating star to have a reflex signal (and thus mass determination) due
to a planetary companion measured.Comment: Accepted to The Astronomical Journa
KELT-6b: A P~7.9 d Hot Saturn Transiting a Metal-Poor Star with a Long-Period Companion
We report the discovery of KELT-6b, a mildly-inflated Saturn-mass planet
transiting a metal-poor host. The initial transit signal was identified in
KELT-North survey data, and the planetary nature of the occulter was
established using a combination of follow-up photometry, high-resolution
imaging, high-resolution spectroscopy, and precise radial velocity
measurements. The fiducial model from a global analysis including constraints
from isochrones indicates that the V=10.38 host star (BD+31 2447) is a mildly
evolved, late-F star with T_eff=6102 \pm 43 K, log(g_*)=4.07_{-0.07}^{+0.04}
and [Fe/H]=-0.28 \pm 0.04, with an inferred mass M_*=1.09 \pm 0.04 M_sun and
radius R_star=1.58_{-0.09}^{+0.16} R_sun. The planetary companion has mass
M_P=0.43 \pm 0.05 M_J, radius R_P=1.19_{-0.08}^{+0.13} R_J, surface gravity
log(g_P)=2.86_{-0.08}^{+0.06}, and density rho_P=0.31_{-0.08}^{+0.07}
g~cm^{-3}. The planet is on an orbit with semimajor axis a=0.079 \pm 0.001 AU
and eccentricity e=0.22_{-0.10}^{+0.12}, which is roughly consistent with
circular, and has ephemeris of T_c(BJD_TDB)=2456347.79679 \pm 0.00036 and
P=7.845631 \pm 0.000046 d. Equally plausible fits that employ empirical
constraints on the host star parameters rather than isochrones yield a larger
planet mass and radius by ~4-7%. KELT-6b has surface gravity and incident flux
similar to HD209458b, but orbits a host that is more metal poor than HD209458
by ~0.3 dex. Thus, the KELT-6 system offers an opportunity to perform a
comparative measurement of two similar planets in similar environments around
stars of very different metallicities. The precise radial velocity data also
reveal an acceleration indicative of a longer-period third body in the system,
although the companion is not detected in Keck adaptive optics images.Comment: Published in AJ, 17 pages, 15 figures, 6 table
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