SEL1L and HRD1 are involved in the degradation of unassembled secretory Ig‐µ chains

Abstract

When expressed in the absence of light chains, secretory Ig-micro chains (micro(s)) undergo endoplasmic reticulum associated degradation (ERAD). This process involves the recognition of terminally misfolded or unassembled molecules, their retro-translocation across the ER membrane and ubiquitination for degradation by cytosolic proteasomes. The molecular components of the ERAD pathway and their coordination remain largely unknown. Here we employed co-immunoprecipitation, silencing or over-expression assays to show that SEL1L and HRD1 are involved in the degradation of unassembled Ig-micro(s), but have minor effects on another substrate, TCR-alpha. SEL1L and HRD1 localize in the early secretory apparatus and are induced by ER stress and during B cell differentiation, concomitantly with the onset of massive IgM secretion. These findings reveal a role for SEL1L and HRD1 in IgM quality control.

Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival

“…Degradation of ER-transmembrane proteins can be Sel1L-Hrd1-independent because of functional redundancy among the ERAD complexes (27). Finally, pointing to a dispensable role of Sel1L in ER homeostasis in vivo, knockdown of Sel1L in cultured cells fails to induce UPR (28,29) and deletion of Hrd3/Sel1 in the fly has no effect on eye size (30). Thus, how Sel1L regulates ERAD and ER homeostasis in vivo remains unclear.…”

Deglycosylation-dependent fluorescent proteins provide unique tools for the study of ER-associated degradation

“…The E3 ubiquitin ligase Hrd1 is required for the ubiquitination and degradation of many ERAD substrates (8,(24)(25)(26)(27)(28)…”

Down-modulation of SEL1L, an Unfolded Protein Response and Endoplasmic Reticulum-associated Degradation Protein, Sensitizes Glioma Stem Cells to the Cytotoxic Effect of Valproic Acid

“…Here we explore the potential therapeutic advantages of VPA treatment combined with perturbation of the proteostasis network on GSC by targeting SEL1L, a crucial modulator of homeostasis (15)(16)(17)43) and linked to neural stemness maintenance and lineage determination (18) as well as cancer aggressiveness (19,21,43).…”

“…SEL1L is an ER-embedded adaptor that links substrate recognition to the E3 ligase-coupled dislocation apparatus (15,16). Considering its accurate timing and control in the proteolysis of key regulators as well as its position between two critical homeostatic pathways, SEL1L regulates several cellular functions and programs including cell fate developmental decision and homeostasis.…”