Distinguishing between retention signals and degrons acting in ERAD

Endoplasmic reticulum-associated degradation (ERAD) eliminates aberrant proteins from the secretory pathway. Such proteins are retained in the endoplasmic reticulum and targeted for degradation by the ubiquitin-proteasome system. Cis-acting motifs can function in ERAD as retention signals, preventing vesicular export from the endoplasmic reticulum, or as degrons, targeting proteins for degradation. Here, we show that µstp, the C-terminal 20-residue tailpiece of the secretory IgM µs heavy chain, functions both as a portable retention signal and as an ERAD degron. Retention of µstp fusions of secreted versions of thyroid peroxidase and yellow fluorescent protein in the endoplasmic reticulum requires the presence of the penultimate cysteine of µstp. In its role as a portable degron, the µstp targets the retained proteins for ERAD but does not serve as an obligatory ubiquitin-conjugation site. Abolishing µstp glycosylation accelerates the degradation of both µstpCys-fused substrates, yet absence of the N-glycan eliminates the requirement for the penultimate cysteine in the retention and degradation of the unglycosylated yellow fluorescent protein. Hence, the dual role played by the µstpCys motif as a retention signal and as a degron can be attributed to distinct elements within this sequence.