LRRC15 suppresses SARS-CoV-2 infection and controls collagen production

Abstract Although ACE2 is the primary receptor for SARS-CoV-2 infection, a systematic assessment of factors controlling SARS-CoV-2 host interactions has not been described. Here we used whole genome CRISPR activation to identify host factors controlling SARS-CoV-2 Spike binding. The top hit was a Toll-like receptor-related cell surface receptor called leucine-rich repeat-containing protein 15 (LRRC15). LRRC15 expression was sufficient to promote SARS-CoV-2 Spike binding where it forms a cell surface complex with LRRC15 but does not support infection. Instead, LRRC15 functioned as a negative receptor suppressing both pseudotyped and live SARS-CoV-2 infection. LRRC15 is expressed in collagen-producing lung myofibroblasts where it can sequester virus and reduce infection in trans. Mechanistically LRRC15 is regulated by TGF-β, where moderate LRRC15 expression drives collagen production but high levels suppress it, revealing a novel lung fibrosis feedback circuit. Overall, LRRC15 is a master regulator of SARS-CoV-2, suppressing infection and controlling collagen production associated with “long-haul” COVID-19.

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LRRC15 suppresses SARS-CoV-2 infection and controls collagen production

10.1101/2021.11.09.467981 ◽

2021 ◽

Author(s):

Lipin Loo ◽

Matthew A. Waller ◽

Alexander J. Cole ◽

Alberto O. Stella ◽

Cesar L. Moreno ◽

...

Keyword(s):

Cell Surface ◽

Cell Surface Receptor ◽

Toll Like Receptor ◽

Collagen Production ◽

Systematic Assessment ◽

Host Interactions ◽

Surface Receptor ◽

A Cell ◽

In Trans ◽

Crispr Activation

Although ACE2 is the primary receptor for SARS-CoV-2 infection, a systematic assessment of factors controlling SARS-CoV-2 host interactions has not been described. Here we used whole genome CRISPR activation to identify host factors controlling SARS-CoV-2 Spike binding. The top hit was a Toll-like receptor-related cell surface receptor called leucine-rich repeat-containing protein 15 (LRRC15). LRRC15 expression was sufficient to promote SARS-CoV-2 Spike binding where it forms a cell surface complex with LRRC15 but does not support infection. Instead, LRRC15 functioned as a negative receptor suppressing both pseudotyped and live SARS-CoV-2 infection. LRRC15 is expressed in collagen-producing lung myofibroblasts where it can sequester virus and reduce infection in trans. Mechanistically LRRC15 is regulated by TGF-β, where moderate LRRC15 expression drives collagen production but high levels suppress it, revealing a novel lung fibrosis feedback circuit. Overall, LRRC15 is a master regulator of SARS-CoV-2, suppressing infection and controlling collagen production associated with "long-haul" COVID-19.

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Faculty Opinions recommendation of A cell surface receptor mediates extracellular Ca(2+) sensing in guard cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005494.201494 ◽

2004 ◽

Author(s):

Ramón Serrano

Keyword(s):

Cell Surface ◽

Guard Cells ◽

Cell Surface Receptor ◽

Surface Receptor ◽

A Cell

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Topological and Structural Plasticity of the Single Ig Fold and the Double Ig Fold Present in CD19

Biomolecules ◽

10.3390/biom11091290 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1290 ◽

Cited By ~ 1

Author(s):

Philippe Youkharibache

Keyword(s):

Cell Surface ◽

3D Structure ◽

Cell Surface Receptor ◽

Cell Surface Receptors ◽

Structural Domain ◽

Surface Receptors ◽

Surface Receptor ◽

In Trans ◽

In Cis ◽

Ig Domain

The Ig fold has had a remarkable success in vertebrate evolution, with a presence in over 2% of human genes. The Ig fold is not just the elementary structural domain of antibodies and TCRs, it is also at the heart of a staggering 30% of immunologic cell surface receptors, making it a major orchestrator of cell–cell interactions. While BCRs, TCRs, and numerous Ig-based cell surface receptors form homo- or heterodimers on the same cell surface (in cis), many of them interface as ligand-receptors (checkpoints) on interacting cells (in trans) through their Ig domains. New Ig-Ig interfaces are still being discovered between Ig-based cell surface receptors, even in well-known families such as B7. What is largely ignored, however, is that the Ig fold itself is pseudosymmetric, a property that makes the Ig domain a versatile self-associative 3D structure and may, in part, explain its success in evolution, especially through its ability to bind in cis or in trans in the context of cell surface receptor–ligand interactions. In this paper, we review the Ig domains’ tertiary and quaternary pseudosymmetries, with particular attention to the newly identified double Ig fold in the solved CD19 molecular structure to highlight the underlying fundamental folding elements of Ig domains, i.e., Ig protodomains. This pseudosymmetric property of Ig domains gives us a decoding frame of reference to understand the fold, relate all Ig domain forms, single or double, and suggest new protein engineering avenues.

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P4-054: KLOTHO ENHANCES NEURONAL ACTIVITY THROUGH INTERACTION WITH A CELL-SURFACE RECEPTOR

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.06.2457 ◽

2006 ◽

Vol 14 (7S_Part_27) ◽

pp. P1453-P1454

Author(s):

Nicola J. Corbett ◽

Kate Fisher ◽

Helen A. Rowland ◽

Alys C. Jones ◽

Nigel M. Hooper

Keyword(s):

Cell Surface ◽

Neuronal Activity ◽

Cell Surface Receptor ◽

Surface Receptor ◽

A Cell

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STRA6, a Cell-Surface Receptor for Retinol-Binding Protein: The Plot Thickens

Cell Metabolism ◽

10.1016/j.cmet.2007.02.006 ◽

2007 ◽

Vol 5 (3) ◽

pp. 164-166 ◽

Cited By ~ 49

Author(s):

William S. Blaner

Keyword(s):

Cell Surface ◽

Binding Protein ◽

Retinol Binding Protein ◽

Cell Surface Receptor ◽

Surface Receptor ◽

A Cell

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230. Megalin, RAP and Nkx3.1 expression in the developing reproductive tract of a marsupial, the tammar wallaby

Reproduction Fertility and Development ◽

10.1071/srb08abs230 ◽

2008 ◽

Vol 20 (9) ◽

pp. 30

Author(s):

M. Gamat ◽

M. B. Renfree ◽

A. J. Pask ◽

G. Shaw

Keyword(s):

Cell Surface ◽

Reproductive Tract ◽

Tammar Wallaby ◽

Cell Surface Receptor ◽

Urogenital Sinus ◽

Receptor Associated Protein ◽

Wide Range ◽

Surface Receptor ◽

A Cell ◽

Strong Staining

Androgens induce the differentiation of the urogenital sinus (UGS) to form a prostate. An early marker of this response is upregulation of the transcription factor Nkx3.1 in the urogenital epithelium in the precursors of prostatic buds. In tammars, prostate differentiation begins ~3 weeks after birth and after the time the testis starts to secrete androgens, and 2 weeks after androgen stimulated Wolffian duct differentiation. The reason for this delay in prostate differentiation is unexplained. Androgen receptors are present in the UGS, and the potent androgen, androstanediol, induces prostatic development in females. Whilst androgens may diffuse into cells by across the cell membrane, there is increasing evidence that steroids are also internalised actively via the cell-surface transport molecule Megalin. We are exploring the possibility that the delay may be related to the establishment of a Megalin-mediated pathway. Megalin is a cell surface receptor expressed on epithelia and mediates the endocytosis of a wide range of ligands, including SHBG-bound sex steroids. Megalin action is regulated by Receptor Associated Protein (RAP), which acts as an antagonist to Megalin action. This study cloned partial sequences of Megalin, RAP and Nkx3.1 and examined their expression in the developing urogenital sinus of the tammar wallaby using RT–PCR. The cellular distribution of Megalin protein in the developing UGS was examined using immunohistochemistry. Megalin, RAP and Nkx3.1 in the tammar were all highly conserved with eutherian orthologueues. Megalin and Nkx3.1 transcripts were detected in the liver, kidney, ovary, testis and developing urogenital sinus of male and female tammars. In the developing UGS of the tammar, there was strong staining for Megalin protein in the urogenital epithelium with some diffuse staining in the surrounding mesenchyme. Together, these results suggest that Megalin could be a key gene in the mediation of androgen action in prostatic development in the tammar wallaby.

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