More Like this

1. TRIM 21‐mediated proteasomal degradation of SAMHD 1 regulates its antiviral activity

   https://doi.org/10.15252/embr.201847528  

   Li, Zhaolong ; Huan, Chen ; Wang, Hong ; Liu, Yue ; Liu, Xin ; Su, Xing ; Yu, Jinghua ; Zhao, Zhilei ; Yu, Xiao‐Fang ; Zheng, Baisong ; et al ( December 2019 , EMBO reports)

   SAMHD1 possesses multiple functions, but whether cellular factors regulateSAMHD1 expression or its function remains not well characterized. Here, by investigating why culturedRDandHEK293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate thatSAMHD1 is a restriction factor for EV71. Importantly, we identifyTRIM21, an E3 ubiquitin ligase, as a key regulator ofSAMHD1, which specifically interacts and degradesSAMHD1 through the proteasomal pathway. However,TRIM21 has no effect on EV71 replication itself. Moreover, we prove that interferon production stimulated by EV71 infection induces increasedTRIM21 andSAMHD1 expression, whereas increasingTRIM21 overridesSAMHD1 inhibition of EV71 in cells and in a neonatal mouse model.TRIM21‐mediated degradation ofSAMHD1 also affectsSAMHD1‐dependent restriction ofHIV‐1 and the regulation of interferon production. We further identify the functional domains inTRIM21 required forSAMHD1 binding and the ubiquitination site K622 inSAMHD1 and show that phosphorylation ofSAMHD1 at T592 also blocks EV71 restriction. Our findings illuminate how EV71 overcomesSAMHD1 inhibition via the upregulation ofTRIM21.

    

   more » « less
2. Disparities exist between the dietary intake of Indigenous Australian women during pregnancy and the Australian dietary guidelines: the Gomeroi gaaynggal study

   https://doi.org/10.1111/jhn.12550  

   Lee, Y. Q. ; Collins, C. E. ; Schumacher, T. L. ; Weatherall, L. J. ; Keogh, L. ; Sutherland, K. ; Gordon, A. ; Rae, K. M. ; Pringle, K. G. ( March 2018 , Journal of Human Nutrition and Dietetics)

   Little is known about the adequacy of nutrient intakes and the overall diet quality of Indigenous Australian pregnant women. The aim of this cross‐sectional study was to assess nutrient sufficiency and diet quality, as measured using the Australian Recommended Food Score (ARFS), in pregnant women from theGomeroi gaaynggalcohort (n= 58).

   Maternal dietary intake during pregnancy was assessed using the Australian Eating Survey Food Frequency Questionnaire, which was self‐administered in the third trimester. Diet quality was determined using theARFS. Food group servings and nutrient intakes were compared to the Australian Guide to Health Eating (AGHE) and Australian Nutrient Reference Values (NRVs). The current analysis examined the adequacy of usual intakes from food sources only, excluding supplements.

   None of the women met allAGHEdaily food group serving recommendations. The highest alignment rates were for dairy (33%), meat/alternatives (31%) and vegetables (29.3%). Almost 93% of participants exceeded the recommended intake of energy‐dense, nutrient‐poor foods and percentage energy from saturated fat was high (15%). Of the five key nutrients for optimal reproductive health (folate, iron, calcium, zinc and fibre), the nutrients with the highest percentage of pregnant women achieving theNRVs were zinc (77.6%) and folate (68.9%), whereas iron was the lowest. Only one person achieved allNRVs (folate, iron, calcium, zinc and fibre) important in pregnancy. The medianARFSwas 28 points (maximum of 73).

   Although the small cohort limits the generalisability of the findings of the present study, the data obtained indicate that the diets of these Indigenous pregnant women are inadequate. Therefore, strategies aiming to optimise nutrient intakes of Indigenous pregnant women are needed urgently.

    

   more » « less
3. Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA‐Sequencing

   https://doi.org/10.1002/art.40772  

   Mahendra, Ankit ; Yang, Xingyu ; Abnouf, Shaza ; Adolacion, Jay R. T. ; Park, Daechan ; Soomro, Sanam ; Roszik, Jason ; Coarfa, Cristian ; Romain, Gabrielle ; Wanzeck, Keith ; et al ( February 2019 , Arthritis & Rheumatology)

   To obtain the comprehensive transcriptome profile of human citrulline‐specific B cells from patients with rheumatoid arthritis (RA).

   Citrulline‐ and hemagglutinin‐specific B cells were sorted by flow cytometry using peptide–streptavidin conjugates from the peripheral blood ofRApatients and healthy individuals. The transcriptome profile of the sorted cells was obtained byRNA‐sequencing, and expression of key protein molecules was evaluated by aptamer‐basedSOMAscan assay and flow cytometry. The ability of these proteins to effect differentiation of osteoclasts and proliferation and migration of synoviocytes was examined by in vitro functional assays.

   Citrulline‐specific B cells, in comparison to citrulline‐negative B cells, from patients withRAdifferentially expressed the interleukin‐15 receptor α (IL‐15Rα) gene as well as genes related to protein citrullination and cyclicAMPsignaling. In analyses of an independent cohort of cyclic citrullinated peptide–seropositiveRApatients, the expression ofIL‐15Rα protein was enriched in citrulline‐specific B cells from the patients’ peripheral blood, and surprisingly, all B cells fromRApatients were capable of producing the epidermal growth factor ligand amphiregulin (AREG). Production ofAREGdirectly led to increased migration and proliferation of fibroblast‐like synoviocytes, and, in combination with anti–citrullinated protein antibodies, led to the increased differentiation of osteoclasts.

   To the best of our knowledge, this is the first study to document the whole transcriptome profile of autoreactive B cells in any autoimmune disease. These data identify several genes and pathways that may be targeted by repurposing severalUSFood and Drug Administration–approved drugs, and could serve as the foundation for the comparative assessment of B cell profiles in other autoimmune diseases.

    

   more » « less
4. Increased PD ‐L1 expression in breast and colon cancer stem cells

   https://doi.org/10.1111/1440-1681.12732  

   Wu, Yanheng ; Chen, Mingshui ; Wu, Peihong ; Chen, Chen ; Xu, Zhi Ping ; Gu, Wenyi ( April 2017 , Clinical and Experimental Pharmacology and Physiology)

   Here we report the expression of programmed cell death ligand 1/2 (PD‐L1/L2) in breast and colon cancer stem cells (CSCs). The stemness of these cells was confirmed by their surface markers. Using flow cytometry analysis we demonstrated thatPD‐L1 expression was higher inCSCs of both cancers compared to non‐stem like cancer cells. Consistent with this, detection of cellularPD‐L1 proteins by western blot assay also showed increasedPD‐L1 protein inCSCs. In contrast, only trace amounts ofPD‐L2 were detected inCSCs of both cancers. Our results suggest that breast and colon cancers may be sensitive toPD1/PD‐L1 immunotherapy and thus warrant further investigations ofCSCtargetedPD1/PD‐L1 therapy.

    

   more » « less
5. Binge Drinking Decreases Corticotropin‐Releasing Factor‐Binding Protein Expression in the Medial Prefrontal Cortex of Mice

   https://doi.org/10.1111/acer.13119  

   Ketchesin, Kyle D. ; Stinnett, Gwen S. ; Seasholtz, Audrey F. ( July 2016 , Alcoholism: Clinical and Experimental Research)

   Dysregulation of the corticotropin‐releasing factor (CRF) system has been observed in rodent models of binge drinking, with a large focus onCRFreceptor 1 (CRF‐R1). The role ofCRF‐binding protein (CRF‐BP), a key regulator ofCRFactivity, in binge drinking is less well understood. In humans, single‐nucleotide polymorphisms inCRHBPare associated with alcohol use disorder and stress‐induced alcohol craving, suggesting a role forCRF‐BPin vulnerability to alcohol addiction.

   The role and regulation ofCRF‐BPin binge drinking were examined in mice exposed to the drinking in the dark (DID) paradigm. Using in situ hybridization, the regulation ofCRF‐BP,CRF‐R1, andCRFmRNAexpression was determined in the stress and reward systems of C57BL/6J mice after repeated cycles ofDID. To determine the functional role ofCRF‐BPin binge drinking,CRF‐BPknockout (CRF‐BP KO) mice were exposed to 6 cycles ofDID, during which alcohol consumption was measured and compared to wild‐type mice.

   CRF‐BPmRNAexpression was significantly decreased in the prelimbic (PL) and infralimbic medial prefrontal cortex (mPFC) of C57BL/6J mice after 3 cycles and in thePLmPFCafter 6 cycles ofDID. No significant changes inCRForCRF‐R1 mRNAlevels were observed in mPFC, ventral tegmental area, bed nucleus of the stria terminalis, or amygdala after 3 cycles ofDID.CRF‐BP KOmice do not show significant alterations in drinking compared to wild‐type mice across 6 cycles of DID.

   These results reveal that repeated cycles of binge drinking alterCRF‐BPmRNAexpression in the mPFC, a region responsible for executive function and regulation of emotion and behavior, including responses to stress. We observed a persistent decrease inCRF‐BPmRNAexpression in the mPFCafter 3 and 6DIDcycles, which may allow for increasedCRFsignaling atCRF‐R1 and contribute to excessive binge‐like ethanol consumption.

    

   more » « less