Biochemistry and Pharmacology - Research Publications

Permanent URI for this collection

http://hdl.handle.net/11343/214

Filters

2020 - 2022 2
2
Reset filters

Settings
Statistics
Citations
Author: Edgington-Mitchell, Laura × Author: Xu, Bangyan × Start date: 2020 × End date: 2024 ×

Search Results

Now showing 1 - 2 of 2
  • Item
    Thumbnail Image
    Ubiquitin-like protein 3 (UBL3) is required for MARCH ubiquitination of major histocompatibility complex class II and CD86
    Liu, H ; Wilson, KR ; Firth, AM ; Macri, C ; Schriek, P ; Blum, AB ; Villar, J ; Wormald, S ; Shambrook, M ; Xu, B ; Lim, HJ ; McWilliam, HEG ; Hill, AF ; Edgington-Mitchell, LE ; Caminschi, I ; Lahoud, MH ; Segura, E ; Herold, MJ ; Villadangos, JA ; Mintern, JD (NATURE PORTFOLIO, 2022-04-11)
    The MARCH E3 ubiquitin (Ub) ligase MARCH1 regulates trafficking of major histocompatibility complex class II (MHC II) and CD86, molecules of critical importance to immunity. Here we show, using a genome-wide CRISPR knockout screen, that ubiquitin-like protein 3 (UBL3) is a necessary component of ubiquitination-mediated trafficking of these molecules in mice and in humans. Ubl3-deficient mice have elevated MHC II and CD86 expression on the surface of professional and atypical antigen presenting cells. UBL3 also regulates MHC II and CD86 in human dendritic cells (DCs) and macrophages. UBL3 impacts ubiquitination of MARCH1 substrates, a mechanism that requires UBL3 plasma membrane anchoring via prenylation. Loss of UBL3 alters adaptive immunity with impaired development of thymic regulatory T cells, loss of conventional type 1 DCs, increased number of trogocytic marginal zone B cells, and defective in vivo MHC II and MHC I antigen presentation. In summary, we identify UBL3 as a conserved, critical factor in MARCH1-mediated ubiquitination with important roles in immune responses.
  • Item
    Thumbnail Image
    Lysosomal degradation products induce Coxiella burnetii virulence
    Newton, P ; Thomas, DR ; Reed, SCO ; Lau, N ; Xu, B ; Ong, SY ; Pasricha, S ; Madhamshettiwar, PB ; Edgington-Mitchell, LE ; Simpson, KJ ; Roy, CR ; Newton, HJ (NATL ACAD SCIENCES, 2020-03-24)
    Coxiella burnetii is an intracellular pathogen that replicates in a lysosome-like vacuole through activation of a Dot/Icm-type IVB secretion system and subsequent translocation of effectors that remodel the host cell. Here a genome-wide small interfering RNA screen and reporter assay were used to identify host proteins required for Dot/Icm effector translocation. Significant, and independently validated, hits demonstrated the importance of multiple protein families required for endocytic trafficking of the C. burnetii-containing vacuole to the lysosome. Further analysis demonstrated that the degradative activity of the lysosome created by proteases, such as TPP1, which are transported to the lysosome by receptors, such as M6PR and LRP1, are critical for C. burnetii virulence. Indeed, the C. burnetii PmrA/B regulon, responsible for transcriptional up-regulation of genes encoding the Dot/Icm apparatus and a subset of effectors, induced expression of a virulence-associated transcriptome in response to degradative products of the lysosome. Luciferase reporter strains, and subsequent RNA-sequencing analysis, demonstrated that particular amino acids activate the C. burnetii PmrA/B two-component system. This study has further enhanced our understanding of C. burnetii pathogenesis, the host-pathogen interactions that contribute to bacterial virulence, and the different environmental triggers pathogens can sense to facilitate virulence.