دورية أكاديمية
أعرض في EDS

Toll like receptor 4 mediates the inhibitory effect of SARS-CoV-2 spike protein on proximal tubule albumin endocytosis.

التفاصيل البيبلوغرافية
العنوان: Toll like receptor 4 mediates the inhibitory effect of SARS-CoV-2 spike protein on proximal tubule albumin endocytosis.
المؤلفون: Silva-Aguiar RP; Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Teixeira DE; Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Peruchetti DB; Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Peres RAS; Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Alves SAS; Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Calil PT; Paulo de Góes Microbiology Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Arruda LB; Paulo de Góes Microbiology Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Costa LJ; Paulo de Góes Microbiology Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Silva PL; Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, Brazil; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil., Schmaier AH; Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; University Hospitals Cleveland Medical Center, Cleveland, OH, USA., Rocco PRM; Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, Brazil; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil., Pinheiro AAS; Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, Brazil., Caruso-Neves C; Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, Brazil; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil. Electronic address: caruso@biof.ufrj.br.
المصدر: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Jun; Vol. 1870 (5), pp. 167155. Date of Electronic Publication: 2024 Apr 04.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101731730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-260X (Electronic) Linking ISSN: 09254439 NLM ISO Abbreviation: Biochim Biophys Acta Mol Basis Dis Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Amsterdam : Elsevier
مواضيع طبية MeSH: Toll-Like Receptor 4*/metabolism , Endocytosis*/drug effects , Kidney Tubules, Proximal*/metabolism , Kidney Tubules, Proximal*/virology , Spike Glycoprotein, Coronavirus*/metabolism , SARS-CoV-2*/metabolism, Humans ; Animals ; HEK293 Cells ; Swine ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphorylation ; COVID-19/metabolism ; COVID-19/virology ; COVID-19/pathology ; Albumins/metabolism ; LLC-PK1 Cells ; Epithelial Cells/metabolism ; Epithelial Cells/virology
مستخلص: Tubular proteinuria is a common feature in COVID-19 patients, even in the absence of established acute kidney injury. SARS-CoV-2 spike protein (S protein) was shown to inhibit megalin-mediated albumin endocytosis in proximal tubule epithelial cells (PTECs). Angiotensin-converting enzyme type 2 (ACE2) was not directly involved. Since Toll-like receptor 4 (TLR4) mediates S protein effects in various cell types, we hypothesized that TLR4 could be participating in the inhibition of PTECs albumin endocytosis elicited by S protein. Two different models of PTECs were used: porcine proximal tubule cells (LLC-PK1) and human embryonic kidney cells (HEK-293). S protein reduced Akt activity by specifically inhibiting of threonine 308 (Thr308) phosphorylation, a process mediated by phosphoinositide-dependent kinase 1 (PDK1). GSK2334470, a PDK1 inhibitor, decreased albumin endocytosis and megalin expression mimicking S protein effect. S protein did not change total TLR4 expression but decreased its surface expression. LPS-RS, a TLR4 antagonist, also counteracted the effects of the S protein on Akt phosphorylation at Thr308, albumin endocytosis, and megalin expression. Conversely, these effects of the S protein were replicated by LPS, an agonist of TLR4. Incubation of PTECs with a pseudovirus containing S protein inhibited albumin endocytosis. Null or VSV-G pseudovirus, used as control, had no effect. LPS-RS prevented the inhibitory impact of pseudovirus containing the S protein on albumin endocytosis but had no influence on virus internalization. Our findings demonstrate that the inhibitory effect of the S protein on albumin endocytosis in PTECs is mediated through TLR4, resulting from a reduction in megalin expression.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: AKT pathway; Albumin endocytosis; Megalin; Proximal tubule; SARS-CoV-2 spike protein; Toll like receptor 4
المشرفين على المادة: 0 (spike protein, SARS-CoV-2)
0 (TLR4 protein, human)
تواريخ الأحداث: Date Created: 20240405 Date Completed: 20240521 Latest Revision: 20240529
رمز التحديث: 20240529
DOI: 10.1016/j.bbadis.2024.167155
PMID: 38579939
قاعدة البيانات: MEDLINE
الوصف
تدمد:1879-260X
DOI:10.1016/j.bbadis.2024.167155