Low pH-triggered beta-propeller switch of the low-density lipoprotein receptor assists rhinovirus infection.
Minor group human rhinoviruses (HRVs) bind three members of the low-density lipoprotein receptor (LDLR) family: LDLR proper, very-LDLR (VLDLR) and LDLR-related protein (LRP). Whereas ICAM-1, the receptor of major group HRVs actively contributes to viral uncoating, LDLRs are rather considered passive vehicles for cargo delivery to the low-pH environment of endosomes. Since the Tyr-Trp-Thr-Asp beta-propeller domain of LDLR has been shown to be involved in the dissociation of bound LDL via intramolecular competition at low pH, we studied whether it also plays a role in HRV infection. Human cell lines deficient in LDLR family proteins are not available. Therefore, we used CHO-ldla7 cells that lack endogenous LDLR. These were stably transfected to express either wild-type (wt) human LDLR or a mutant with a deletion of the beta-propeller. When HRV2 was attached to the propeller-negative LDLR, a lower pH was required for conversion to subviral particles than when attached to wt LDLR. This indicates that high-avidity receptor binding maintains the virus in its native conformation. HRV2 internalization directed the mutant LDLR but not wt LDLR to lysosomes, resulting in reduced plasma membrane expression of propeller-negative LDLR. Infection assays using a CHO-adapted HRV2 variant showed a delay in intracellular viral conversion and de novo viral synthesis in cells expressing the truncated LDLR. Our data indicate that the beta-propeller attenuates the virus-stabilizing effect of LDLR binding and thereby facilitates RNA release from endosomes, resulting in the enhancement of infection. This is a nice example of a virus exploiting high-avidity multimodule receptor binding with an intrinsic release mechanism.
Konecsni
Tuende
T
Max F. Perutz Laboratories, University Department at the Vienna Biocenter, Medical University of Vienna, Vienna, Austria.
Berka
Ursula
U
Pickl-Herk
Angela
A
Bilek
Gerhard
G
Khan
Abdul Ghafoor
AG
Gajdzig
Leszek
L
Fuchs
Renate
R
Blaas
Dieter
D
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008077:Lipoproteins, LDL / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D009154:Mutation; D010850:Picornaviridae Infections / Q000378:metabolism*; D017433:Protein Structure, Secondary; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012229:Rhinovirus / Q000502:physiology*; D053585:Virus Attachment; D053586:Virus Internalization
D008077:Lipoproteins, LDL; D012367:RNA, Viral; D011973:Receptors, LDL
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