Multiple cytosolic innate sensors form large signalosomes after activation, but this assembly needs to be tightly regulated to avoid accumulation of misfolded aggregates. We found that the eIF2α kinase heme-regulated inhibitor (HRI) controls NOD1 signalosome folding and activation through a process requiring eukaryotic initiation factor 2α (eIF2α), the transcription factor ATF4, and the heat shock protein HSPB8. The HRI/eIF2α signaling axis was also essential for signaling downstream of the innate immune mediators NOD2, MAVS, and TRIF but dispensable for pathways dependent on MyD88 or STING. Moreover, filament-forming α-synuclein activated HRI-dependent responses, which suggests that the HRI pathway may restrict toxic oligomer formation. We propose that HRI, eIF2α, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms, functionally homologous to the PERK/eIF2α/HSPA5 axis of the endoplasmic reticulum UPR.

The human APOBEC3 family of DNA cytosine deaminases serves as a front-line intrinsic immune response to inhibit the replication of diverse retroviruses. APOBEC3F and APOBEC3G are the most potent factors against HIV-1. As a countermeasure, HIV-1 viral infectivity factor (Vif) targets APOBEC3s for proteasomal degradation. Here, we report the crystal structure of the Vif-binding domain in APOBEC3F and a novel assay to assess Vif-APOBEC3 binding. Our results point to an amphipathic surface that is conserved in APOBEC3s as critical for Vif susceptibility in APOBEC3F. Electrostatic interactions likely mediate Vif binding. Moreover, structure-guided mutagenesis reveals a straight ssDNA-binding groove distinct from the Vif-binding site, and a novel ‘aromatic switch’ is proposed to explain DNA substrate specificities across the APOBEC3 family. This study opens new lines of inquiry that will further our understanding of APOBEC3-mediated retroviral restriction and provides an accurate template for structure-guided development of inhibitors targeting the APOBEC3-Vif axis.

The current World Health Organization classification divides endometrial sarcomas into low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma. Recent studies suggest undifferentiated endometrial sarcoma is a heterogeneous group and a subgroup with uniform nuclei is more akin to lowgrade endometrial stromal sarcoma in terms of morphologic, immunohistochemical and genetic features. We classified endometrial sarcomas treated at our institution from 1998 to 2011 into low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma, the latter being further categorized into a group with either uniform or pleomorphic nuclei. Morphological features, immunoprofile and fluorescence in situ hybridization rearrangements of JAZF1 and PHF1 genes were correlated with tumor category and outcome. A total of 40 cases were evaluated comprising 23 low-grade endometrial stromal sarcomas, 10 undifferentiated endometrial sarcomas with nuclear uniformity and 7 undifferentiated endometrial sarcomas with nuclear pleomorphism. Low-grade endometrial stromal sarcomas were more often estrogen and progesterone receptor positive (83%) compared with undifferentiated endometrial sarcoma with nuclear uniformity (10%) or with nuclear pleomorphism (0%) (Po0.001). Positivity for p53 was restricted to undifferentiated endometrial sarcomas with more frequent expression in the group with nuclear pleomorphism (57%) than with nuclear uniformity (10%) (P ¼ 0.06). Ki-67 proliferation index in 410% of tumor cells more frequent in undifferentiated endometrial sarcoma than low-grade endometrial stromal sarcoma (P ¼ o0.001). JAZF1 rearrangement was detected in 32% of low-grade endometrial stromal sarcomas and in none of the undifferentiated sarcomas. Rearrangement of PHF1 was found in two patients, one with JAZF1 À PHF1 fusion. There were no significant differences in clinical behavior between undifferentiated endometrial sarcoma with nuclear uniformity versus nuclear pleomorphism. In conclusion, we found undifferentiated endometrial sarcoma subtypes and low-grade endometrial stromal sarcoma have distinct immunohistochemical and cytogentic profiles. Our data do not show any difference in clinical behavior between subgroups in undifferentiated sarcomas. Modern Pathology (2013) 26, 95-105;

Human immunodeficiency virus (HIV) is a retroviral pathogen that targets human immune cells such as CD4 + T cells, macrophages, and dendritic cells. The human apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3 or A3) cytidine deaminases are a key class of intrinsic restriction factors that inhibit replication of HIV. When HIV-1 enters the cell, the immune system responds by inducing the activation of the A3 family proteins, which convert cytosines to uracils in singlestranded DNA replication intermediates, neutralizing the virus. HIV counteracts this intrinsic immune response by encoding a protein termed viral infectivity factor (Vif). Vif targets A3 to an E3 ubiquitin ligase complex for poly-ubiquitination and proteasomal degradation. Vif is unique in that it can recognize and counteract multiple A3 restriction factor substrates. Structural biology studies have provided significant insights into the overall architectures and functions of Vif and A3 proteins; however, a structure of the Vif-A3 complex has remained elusive. In this review, we summarize and reanalyze experimental data from recent structural, biochemical, and functional studies to provide key perspectives on the residues involved in Vif-A3 protein-protein interactions.

ObjectivesOne quarter of HIV-1 positive individuals in Sweden present for care with HIV or AIDS associated conditions without an HIV test (missed presentations) and 16% report neglect of such symptoms. The objective of this study was to identify risk factors for these missed opportunities of HIV-1 diagnosis.MethodsA national study, recruiting 409 newly diagnosed HIV-1 infected adults over a 2.5-year period, was performed. Logistic regression models tested the relationship between missed presentation and patient’s neglect versus socio-demographic and behavioural risk factors. Additionally the initiator of the HIV test was assessed.ResultsThe odds for a missed presentation was lower for migrants (from East Europe, Asia, and Pacific (East): OR 0.4 (0.2–0.8); Sub-Saharan Africa (SSA): 0.3 (0.2–0.6); other: 0.5 (0.2–1.0)), compared to patients born in Sweden, just as symptoms neglected by the patient (East (0.3 (0.1–1.0); SSA (0.4 (0.2–0.8)). The latter was also lower for men who have sex with men (0.5 (0.2–1.0)), compared to patients infected heterosexually. Patients infected in the East, with present/previous substance use or a previous negative HIV test were more likely to take the initiative to test on their own, whereas those >50 years and with a previously missed presentation had significantly reduced odds, p<0.05.ConclusionsIndividuals without epidemiological indicators of HIV are more likely to have a history of missed presentations, to neglect symptoms and are less prone to take an initiative to test for HIV themselves. It is important to further implement testing to include all patients with symptoms and conditions indicative of HIV.