ERAD ubiquitin ligases

Abstract

In eukaryotic cells terminally misfolded proteins of the secretory pathway are retarded in the endoplasmic reticulum (ER) and subsequently degraded in a ubiquitin-proteasome-dependent manner. This highly conserved process termed ER-associated protein degradation (ERAD) ensures homeostasis in the secretory pathway by disposing faulty polypeptides and preventing their deleterious accumulation and eventual aggregation in the cell. The focus of this paper is the functional description of membrane-bound ubiquitin ligases, which are involved in all critical steps of ERAD. In the end we want to speculate on how the modular architecture of these entities ensures the specificity of substrate selection and possibly accomplishes the transport of misfolded polypeptides from the ER into the cytoplasm.

RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation

“…The substrates for some of these mammalian ligases are known (for example, TRC8 ubiquitinates MHC class I (23)), and it seems likely that each may target a fairly restricted group of substrates. This contrasts with the situation in yeast, where the ER contains only two E3 ligases, Hrd1p and Doa10, which, via adapters, mediate the processing of a broad range of substrates (11)(12)(13). It is noteworthy that we previously investigated several of these mammalian E3 ligases (Hrd1, gp78, TEB4, and RNF5) for a role in IP 3 receptor processing using RNA interference, but depletion of none had a significant effect on IP 3 receptor ubiquitination or degradation 4 .…”

“…This was confirmed by experiments showing that RNF170 is an integral membrane protein and that it has an ER-like distribution pattern. RNF170 can thus be added to the list of known mammalian ER membrane E3 ligases (13,20). These include Hrd1 and gp78 (the mammalian homologs of yeast Hrd1p) (11,13), TEB4 (the mammalian homolog of yeast Doa10) (11,13), RNF5 (21), Kf-1 (22), TRC8 (23), RNF121 (17), RNF122 (24), and RNF180 (25).…”

“…RNF170 can thus be added to the list of known mammalian ER membrane E3 ligases (13,20). These include Hrd1 and gp78 (the mammalian homologs of yeast Hrd1p) (11,13), TEB4 (the mammalian homolog of yeast Doa10) (11,13), RNF5 (21), Kf-1 (22), TRC8 (23), RNF121 (17), RNF122 (24), and RNF180 (25). The substrates for some of these mammalian ligases are known (for example, TRC8 ubiquitinates MHC class I (23)), and it seems likely that each may target a fairly restricted group of substrates.…”

“…A good deal is known about the enzymes, particularly the E3s, that catalyze ERAD substrate ubiquitination (11)(12)(13), and it has also been established that a cytosolic complex composed of the ATPase p97 and its cofactors Ufd1 and Npl4 mediates the transfer of ERAD substrates to the proteasome (11). This p97-Ufd1-Npl4 complex participates in the delivery of polyubiquitinated IP 3 receptors to the proteasome (4).…”

The prolific ATL family of RING-H2 ubiquitin ligases

“…ERAD is a cellular process that targets misfolded proteins on the ER for ubiquitination. 35 It has been proposed that a negative regulator of defense response or an unknown unfolded stress protein induced during ERAD may be targets of the E3 ligase AthATL9, which would function in the ER lumen. 36 EL5 has been extensively investigated, and the RING-H2 finger domain has been used as a model to analyze three-dimensional structures as well as interactions with the E2 enzyme.…”