Insulin-Like Growth Factor 2 Receptor Expression Is Promoted by Human Herpesvirus 8-Encoded Interleukin-6 and Contributes to Viral Latency and Productive Replication.
Cathepsin D
/ metabolism
Cell Line, Tumor
Cell Proliferation
/ genetics
Cell Survival
/ genetics
Cytokine Receptor gp130
/ metabolism
Endoplasmic Reticulum
/ metabolism
Endothelial Cells
/ virology
Enzyme Precursors
/ metabolism
HEK293 Cells
Herpesvirus 8, Human
/ metabolism
Humans
Interleukin-6
/ metabolism
Lymphoma, Primary Effusion
/ virology
Mannosephosphates
/ metabolism
Receptor, IGF Type 2
/ biosynthesis
Ubiquitination
Virus Activation
/ genetics
Virus Latency
/ genetics
Virus Replication
/ genetics
Vitamin K Epoxide Reductases
/ metabolism
ER-associated degradation
cation-independent mannose-6-phosphate receptor
endoplasmic reticulum
human herpesvirus 8
insulin-like growth factor 2 receptor
latency
replication
viral interleukin-6
vitamin K epoxide reductase complex subunit 1 variant-2
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
01 03 2019
01 03 2019
Historique:
received:
12
11
2018
accepted:
29
11
2018
pubmed:
14
12
2018
medline:
21
11
2019
entrez:
14
12
2018
Statut:
epublish
Résumé
Human herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6) localizes largely to the endoplasmic reticulum (ER) and here associates functionally with both the gp130 signal transducer and the novel ER membrane protein vitamin K epoxide reductase complex subunit 1 variant-2 (VKORC1v2). The latter interaction contributes to the viability of latently infected primary effusion lymphoma (PEL) cells and to HHV-8 productive replication, in part via promotion of ER-associated degradation (ERAD) of nascent pro-cathepsin D (pCatD) and consequent suppression of lysosome-localized proapoptotic mature CatD. Here we report that VKORC1v2 associates with insulin-like growth factor 2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor, which is involved in trafficking of mannose-6-phosphate-conjugated glycoproteins to lysosomes. VKORC1v2 effected reduced IGF2R expression in a manner dependent on VKORC1v2-IGF2R interaction, while vIL-6, which could inhibit VKORC1v2-IGF2R interaction, effected increased expression of IGF2R. These effects were independent of changes in IGF2R mRNA levels, indicating likely posttranslational mechanisms. In kinetic analyses involving labeling of either newly synthesized or preexisting IGF2R, vIL-6 promoted accumulation of the former while having no detectable effect on the latter. Furthermore, vIL-6 led to decreased K48-linked ubiquitination of IGF2R and suppression of ERAD proteins effected increased IGF2R expression and loss of IGF2R regulation by vIL-6. Depletion-based experiments identified IGF2R as a promoter of PEL cell viability and virus yields from lytically reactivated cultures. Our findings identify ER-transiting nascent IGF2R as an interaction partner of VKORC1v2 and target of vIL-6 regulation and IGF2R as a positive contributor to HHV-8 biology, thereby extending understanding of the mechanisms of VKORC1v2-associated vIL-6 function.
Identifiants
pubmed: 30541844
pii: JVI.02026-18
doi: 10.1128/JVI.02026-18
pmc: PMC6384062
pii:
doi:
Substances chimiques
Enzyme Precursors
0
IGF2R protein, human
0
Interleukin-6
0
Mannosephosphates
0
Receptor, IGF Type 2
0
Cytokine Receptor gp130
133483-10-0
mannose-6-phosphate
3672-15-9
VKORC1 protein, human
EC 1.17.4.4
Vitamin K Epoxide Reductases
EC 1.17.4.4
procathepsin D
EC 3.4.23.-
Cathepsin D
EC 3.4.23.5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R01 CA076445
Pays : United States
Informations de copyright
Copyright © 2019 American Society for Microbiology.
Références
Biochim Biophys Acta. 2009 Apr;1793(4):605-14
pubmed: 19046998
J Biol Chem. 1985 Aug 5;260(16):9435-42
pubmed: 2991246
Oncogene. 1999 Jul 15;18(28):4063-8
pubmed: 10435587
Cells. 2014 Aug 05;3(3):824-47
pubmed: 25100021
J Biol Chem. 2014 Jun 20;289(25):17941-50
pubmed: 24811165
ACS Chem Biol. 2008 Jun 20;3(6):373-82
pubmed: 18533659
J Virol. 2012 Feb;86(3):1577-88
pubmed: 22130532
Vitam Horm. 2009;80:667-97
pubmed: 19251055
J Virol. 1999 Oct;73(10):8268-78
pubmed: 10482577
J Virol. 2014 Oct;88(20):12167-72
pubmed: 25078695
J Biol Chem. 1999 Aug 27;274(35):24685-93
pubmed: 10455136
J Biol Chem. 1995 Jun 23;270(25):14975-82
pubmed: 7797478
PLoS Pathog. 2010 Aug 05;6(8):e1001031
pubmed: 20700448
J Virol. 2009 Jan;83(2):722-33
pubmed: 18987143
J Virol. 2012 Sep;86(18):9708-20
pubmed: 22740391
PLoS Pathog. 2012;8(6):e1002748
pubmed: 22685405
J Virol. 2014 Jan;88(2):1025-38
pubmed: 24198402
J Virol. 2018 Mar 14;92(7):
pubmed: 29343584
J Biol Chem. 2004 Sep 10;279(37):38658-67
pubmed: 15252023
Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):580-4
pubmed: 1846448
J Virol. 2007 Aug;81(15):8050-62
pubmed: 17507477
J Biol Chem. 1990 Apr 25;265(12):6650-5
pubmed: 1969863
Cancer Lett. 2010 Mar 1;289(1):11-22
pubmed: 19646808
J Virol. 2003 Apr;77(7):4205-20
pubmed: 12634378
BMC Cancer. 2002 Jul 30;2:18
pubmed: 12149131
J Virol. 2000 Nov;74(21):10187-93
pubmed: 11024147
J Virol. 2017 Oct 27;91(22):
pubmed: 28878084
Biochim Biophys Acta. 1995 Jul 17;1241(2):177-94
pubmed: 7640295
J Virol. 2015 Aug;89(15):7979-90
pubmed: 26018151
Curr Opin Cell Biol. 2018 Aug;53:22-28
pubmed: 29719269
Mol Biol Cell. 2015 Dec 1;26(24):4438-50
pubmed: 26424800
Int J Oncol. 2014 Sep;45(3):1241-9
pubmed: 24968760
J Cell Sci. 1997 Apr;110 ( Pt 8):1023-32
pubmed: 9152028
J Virol. 2013 Oct;87(19):10816-27
pubmed: 23903842