Proteasomal degradation of preemptive quality control (pQC) substrates is mediated by an AIRAPL–p97 complex

Braunstein, Ilana; Zach, Lolita; Allan, Susanne; Kalies, Kai‐Uwe; Stanhill, Ariel

doi:10.1091/mbc.e15-02-0085

Cited by 28 publications

(29 citation statements)

References 46 publications

(93 reference statements)

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“…While mutations in AIRAPL that eliminate binding to p97 do not impair its ability to bind Bag6 and ubiquitin ( Yun et al, 2008 ), we demonstrate that specific binding of AIRAPL to Lys48-linked ubiquitin chains is required for its interaction with both Bag6 and the proteasome ( Fig. 5 ) as well as pre-emptive quality control substrates that are designated for proteasomal degradation ( Braunstein et al, 2015 ). Therefore, the selective binding of AIRAPL to Lys48-linked poly-ubiquitin chains is not surprising as these chains are considered the canonical targeting signals for the proteasome ( Ciechanover and Stanhill, 2014 ).…”

Section: Discussionmentioning

confidence: 71%

“…AIRAPL is a p97 adaptor that has been demonstrated to bind Bag6 and the proteasome ( Glinka et al, 2013 , Yun et al, 2008 ) and is involved in the proteasomal processing of pre-emptive quality control substrates ( Braunstein et al, 2015 ). Functional impairment of AIRAPL homologues is linked to the acceleration of ageing and protein aggregation ( Yun et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

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Selective Binding of AIRAPL Tandem UIMs to Lys48-Linked Tri-Ubiquitin Chains

et al. 2016

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Lys48-linked ubiquitin chains act as the main targeting signals for protein degradation by the proteasome. Here we report selective binding of AIRAPL, a protein that associates with the proteasome upon exposure to arsenite, to Lys48-linked tri-ubiquitin chains. AIRAPL comprises two ubiquitin-interacting motifs in tandem (tUIMs) that are linked through a flexible inter-UIM region. In the complex crystal structure UIM1 binds the proximal ubiquitin, whereas UIM2 (the double-sided UIM) binds non-symmetrically to the middle and distal ubiquitin moieties on either side of the helix. Specificity of AIRAPL for Lys48-linked ubiquitin chains is determined by UIM2, and the flexible inter-UIM linker increases avidity by placing the two UIMs in an orientation that facilitates binding of the third ubiquitin to UIM1. Unlike middle and proximal ubiquitins, distal ubiquitin binds UIM2 through a novel surface, which leaves the Ile44 hydrophobic patch accessible for binding to the proteasomal ubiquitin receptors.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Selective Binding of AIRAPL Tandem UIMs to Lys48-Linked Tri-Ubiquitin Chains

et al. 2016

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“…Mislocalized proteins are selectively degraded by the proteasome 34 . This type of cytoplasmic, non-ERAD degradation machinery for ER proteins has been defined as a preemptive quality control system, which can be fine-tuned to reduce the efficiency of translocation during ER stress in an SS-sequence-specific manner 6 – 8 , 51 .…”

Section: Discussionmentioning

confidence: 99%

“…We also recently reported that the signal sequence (SS)-truncated (and thus artificially mislocalized) single-pass TM protein IL-2Rα is captured by the UBQLN4/BAG6 complex in an unembedded TMD-dependent manner 4 . BAG6 is a hydrophobicity-oriented chaperone/holdase 18 – 24 that has been shown to be a receptor for tail-anchored (TA) protein biogenesis 25 – 31 and for targeted degradation of newly synthesized defective polypeptides with exposed hydrophobicity in the cytosol 2 , 7 , 19 , 20 , 32 – 34 . However, the critical functions of BAG6 in the elimination of the SS-uncleaved form of mislocalized TMD proteins have not been adequately proven and further experimental verification is awaited.…”

Section: Introductionmentioning

confidence: 99%

Elimination of a signal sequence-uncleaved form of defective HLA protein through BAG6

Yamamoto

Hayashishita

Minami

et al. 2017

Sci Rep

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A portion of newly synthesized transmembrane domain proteins tend to fail to assemble correctly in the lumen of the endoplasmic reticulum, thus resulting in the production of a signal sequence-uncleaved form of the defective species. Although the efficient degradation of these mistargeted polypeptides is crucial, the molecular mechanism of their elimination pathway has not been adequately characterized. In this study, we focused on one such cryptic portion of a defective transmembrane domain protein, HLA-A, and show that a part of HLA-A is produced as a signal sequence-uncleaved labile species that is immediately targeted to the degradation pathway. We found that both BAG6 and proteasomes are indispensable for elimination of mislocalized HLA-A species. Furthermore, defective HLA-A is subjected to BAG6-dependent solubilization in the cytoplasm. These observations suggest that BAG6 acts as a critical factor for proteasome-mediated degradation of mislocalized HLA-A with a non-cleaved signal sequence at its N-terminus.

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“…The proposed mechanism agrees with recent evidences that have demonstrated the implication of AIRAPL in pre-emptive quality control (PQC) pathway. 6 Accordingly, we propose that AIRAPL-dependent PQC activity promotes translocation of IGF1R nascent polypeptides out of the ER and their proteasome-mediated degradation. Although AIR-APL is unlikely to display E3-ligase activity, we have found that its overexpression is sufficient to promote IGF1R ubiquitination.…”

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confidence: 98%