Human cytomegalovirus uses an E3 ubiquitin ligase to divert MHC I molecules into the ER-associated degradation pathway for destruction

Blom

Boyle

Brauweiler

Chen

Chevalier

Dick van den Boomen

Emmanuel J.H.J. Wiertz

Fiebiger

Furman

Gemmill

Harry A. Drabkin

Hassink

Helen R. Stagg

Hirsch

Hughes

Kikkert

Kostova

Kreft

Lilley

Loureiro

Mair Thomas

Mueller

Paul J. Lehner

Ploegh

Poland

Robert M. Gemmill

Shamu

Strausberg

Vembar

Wiertz

Younger

English

PubMed

The US2 and US11 gene products of human cytomegalovirus promote viral evasion by hijacking the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. US2 and US11 initiate dislocation of newly translocated major histocompatibility complex class I (MHC I) from the ER to the cytosol for proteasome-mediated degradation, thereby decreasing cell surface MHC I. Despite being instrumental in elucidating the mammalian ERAD pathway, the responsible E3 ligase or ligases remain unknown. Using a functional small interfering RNA library screen, we now identify TRC8 (translocation in renal carcinoma, chromosome 8 gene), an ER-resident E3 ligase previously implicated as a hereditary kidney cancer gene, as required for US2-mediated MHC I ubiquitination. Depletion of TRC8 prevents MHC I ubiquitination and dislocation by US2 and restores cell surface MHC I. TRC8 forms an integral part of a novel multiprotein ER complex that contains MHC I, US2, and signal peptide peptidase. Our data show that the TRC8 E3 ligase is required for MHC I dislocation from the ER and identify a new complex associated with mammalian ERAD.</p

Stagg, Helen R

Thomas, Mair

van den Boomen, Dick

Wiertz, Emmanuel J H J

Drabkin, Harry A

Gemmill, Robert M

Lehner, Paul J

Edinburgh Research Explorer

The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER

Crossref

A glycosylated type I membrane protein becomes cytosolic when peptide: N-glycanase is compromised.

Human cytomegalovirus US3 chimeras containing US2 cytosolic residues acquire major histocompatibility class I and II protein degradation properties.

Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum.

Membrane-specific, hostderived factors are required for US2- and US11-mediated degradation of major histocompatibility complex class I molecules.

Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome.

RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene.

Selective export of HLA-F by its cytoplasmic tail.

The activity of a human endoplasmic reticulum-associated degradation E3, gp78, requires its Cue domain, RING finger, and an E2-binding site.

The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8.

The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway.

The ubiquitylation machinery of the endoplasmic reticulum.

Ubiquitination of MHC class I heavy chains is essential for dislocation by human cytomegalovirus-encoded US2 but not US11.

Ubiquitinylation of the cytosolic domain of a type I membrane protein is not required to initiate its dislocation from the endoplasmic reticulum.

Visualization of the ER-to-cytosol dislocation reaction of a type I membrane protein.

http://jcb.rupress.org/content/jcb/186/5/685.full.pdf

The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER

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