SGTA antagonizes BAG6-mediated protein triage

Abstract

The BAG6 complex was first identified as an upstream loading factor for tail-anchored membrane proteins entering the TRC40-dependent pathway for posttranslational delivery to the endoplasmic reticulum. Subsequently, BAG6 was shown to enhance the proteasomal degradation of mislocalized proteins by selectively promoting their ubiquitination. We now show that the BAG6-dependent ubiquitination of mislocalized proteins is completely reversible and identify a pivotal role for the small glutamine-rich tetratricopeptide repeatcontaining protein α (SGTA) in specifically antagonizing this process. SGTA does not simply mask the exposed hydrophobic transmembrane domain of a mislocalized protein, thereby preventing BAG6 recruitment. Rather, SGTA actively promotes the deubiquitination of mislocalized proteins that are already covalently modified, thus reversing the actions of BAG6 and inhibiting its capacity to promote substrate-specific degradation. This SGTA-mediated effect is independent of its tetratricopeptide motifs, suggesting it does not require the actions of Hsp70 and Hsp90 chaperones. These data reveal that, in a cellular context, mislocalized protein ubiquitination is the result of a dynamic equilibrium reflecting competition between pathways that promote either protein maturation or degradation. The targeted perturbation of this equilibrium, achieved by increasing steady-state SGTA levels, results in a specific stabilization of a model mislocalized protein derived from the amyloid precursor protein, an effect that is completely negated by ensuring efficient precursor delivery to the endoplasmic reticulum. We speculate that a BAG6/ SGTA cycle operates during protein maturation and quality control in the cytosol and that together these components dictate the fate of a specific subset of newly synthesized proteins. membrane protein targeting | protein homeostasis

Structural and Functional Characterization of Ybr137wp Implicates Its Involvement in the Targeting of Tail-Anchored Proteins to Membranes

“…The TPR domain of Sgt2 is also involved in the homeostasis of other proteins (54,55). A recent study revealed that Sgt2 interacts with two key chaperones (Ssa1 and Hsp104) involved in prion pathogenesis and affects prion formation in yeast (56).…”

“…A recent study revealed that Sgt2 interacts with two key chaperones (Ssa1 and Hsp104) involved in prion pathogenesis and affects prion formation in yeast (56). Furthermore, the mammalian homolog of Sgt2, SGTA, antagonized the Bag6-dependent ubiquitination of mislocalized proteins (55). The protein interaction networks and the time when the gene is expressed often provide strong clue to its biological function.…”

Bag6 complex contains a minimal tail-anchor–targeting module and a mock BAG domain

“…In yeast, these two proteins form a heterotetramer that regulates the handoff of the TA protein from the cochaperone small, glutamine-rich, tetratricopeptide repeat protein 2 (Sgt2) [small glutamine-rich tetratricopeptide repeat-containing protein (SGTA) in mammals] to the delivery factor Get3 (TRC40 in mammals) (19)(20)(21)(22). It is expected that the mammalian homologs, along with Bag6, play a similar role (23)(24)(25)(26)(27). Bag6 also interacts with other proteins such as apoptosisinducing factor, glycoprotein 78 (gp78), regulatory particle 5, and brother of regulator of imprinted sites (BORIS) (16,(27)(28)(29)(30)(31)(32) and can homo-oligomerize, increasing the level of complexity (30).…”

The Cochaperone SGTA (Small Glutamine-rich Tetratricopeptide Repeat-containing Protein Alpha) Demonstrates Regulatory Specificity for the Androgen, Glucocorticoid, and Progesterone Receptors

“…However, the role of SGTA in protein triage is intriguing. SGTA was recently shown to antagonize BAG6-mediated protein triage by promoting deubiquitination of substrates leading to the stabilization of mislocalized proteins (43). Although the role of SGTA in BAG6-mediated protein triage is independent of the TPR domain and interaction with Hsp70 and Hsp90, these findings provide a direct link between SGTA and a role in the stabilization of proteins.…”