Abstract
During endoplasmic reticulum (ER)-associated degradation (ERAD), a relatively small number of ubiquitin ligases (E3) must be capable of ubiquitinating an assortment of substrates diverse in both structure and location (ER lumen, membrane, and/or cytosol). Therefore, mechanisms that operate independently of primary sequence determinants must exist to ensure specificity during this process. Here we provide direct evidence for adapter-mediated substrate recruitment for a virus-encoded ERAD E3 ligase, mK3. Members of an ER membrane protein complex that normally functions during major histocompatibility complex class I biogenesis in the immune system are required for mK3 substrate selection. We demonstrate that heterologous substrates could be ubiquitinated by mK3 if they were recruited by these ER accessory molecules to the proper position relative to the ligase domain of mK3. This mechanism of substrate recruitment by adapter proteins may explain the ability of some E3 ligases, including cellular ERAD E3 ligases, to specifically target the ubiquitination of multiple substrates that are unrelated in sequence.
Highlights
Ubiquitin-regulated pathways intersect with virtually all aspects of cell biology
The degradation pathway downstream from mK3 has clear similarities to endoplasmic reticulum (ER)-associated degradation (ERAD) induced by cellular E3 ligases because many of the same molecules are involved [30]
Class I molecules are comprised of a type I transmembrane protein, the heavy chains (HC), and a soluble light chain (2m), which assemble in the ER lumen along with a peptide antigen
Summary
Ubiquitin-regulated pathways intersect with virtually all aspects of cell biology. This is certainly true of protein quality control pathways, including those that operate to degrade proteins from the ER2 lumen and membrane. ERAD Substrate Recruitment by Adapter Proteins plex for stable expression, led to an alternative model to explain the specificity of mK3 for MHC class I HC; the association of mK3 with TAP-1/2 and tapasin positions its RING-CH domain such that only the tail of class I HC but not the cytosolic domains of other proteins within the peptide-loading complex can be ubiquitinated [21].
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