ATP13A1 prevents ERAD of folding-competent mislocalized and misoriented proteins

McKenna, Michael J.; Adams, Benjamin M.; Chu, Victor C.; Paulo, João A.; Shao, Sichen

doi:10.1016/j.molcel.2022.09.035

Cited by 21 publications

(36 citation statements)

References 80 publications

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“…The EMC is the major insertase for ER TAs with lower hydrophobicity TMDs, which are similar to those of mitochondrial TAs. Consistent with this biophysical similarity, we and others have demonstrated that the EMC is responsible for misinsertion of mitochondrial TAs into the ER (Figures 1B-C, S1A-B; Guna et al, 2022b; McKenna et al, 2022). Using an established split GFP system to specifically query TA integration into the ER (Inglis et al, 2020), we found that multiple mitochondrial TAs were misinserted in an EMC, but not WRB/CAML, dependent manner (Figures 1C and S1A-B).…”

Section: Resultssupporting

confidence: 89%

A selectivity filter in the EMC limits protein mislocalization to the ER

Pleiner

Hazu

Tomaleri

et al. 2022

Preprint

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Tail anchored proteins (TAs) play essential roles at both the ER and mitochondria, and their accurate localization is critical to proteostasis. Biophysical similarities lead to mistargeting of mitochondrial TAs to the ER, where they are delivered to the ER membrane protein complex (EMC). We showed that the EMC directly contributes to sorting fidelity of mitochondrial TAs and multipass substrates that contain positively charged soluble domains. Leveraging an improved structural model of the human EMC, we used mutagenesis and site-specific crosslinking to map the path of a TA from its cytosolic capture by methionine-rich loops to its membrane insertion through a hydrophilic vestibule. Positively charged residues at the entrance to the vestibule function as a selectivity filter that uses charge-repulsion to reject mitochondrial TAs. Substrate discrimination by the EMC provides a biochemical explanation for one role of charge in TA sorting and protects compartment identity by limiting protein misinsertion.

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Section: Resultssupporting

confidence: 89%

A selectivity filter in the EMC limits protein mislocalization to the ER

Pleiner

Hazu

Tomaleri

et al. 2022

Preprint

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“…At first glance, the dynamic exchange of membrane proteins between organelles would appear paradoxical. However, growing evidence suggests that kinetically driven cycles of insertion and extraction-rather than a single, high-fidelity insertion event-best explain the observed, steady-state partitioning of many membrane proteins [28][29][30][31][32][33] . Perturbing this cycle results in the aberrant accumulation of TA proteins at incorrect membranes.…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial TA proteins that mislocalize to the ER are recognized by ATP13A1 (Spf1 in yeast), an ER-resident ATPase functionally analogous to ATAD1/Msp1 in the OMM 29,33 .…”

Section: Discussionmentioning

confidence: 99%

“…In the ER membrane, TA proteins are inserted by either the 'guided entry of TA proteins' (GET) pathway or the 'ER membrane protein complex' (EMC), while mislocalized or aberrant TA proteins are extracted by ATP13A1 (Spf1 in yeast) [25][26][27] . Far from futile, dynamic cycles of TA protein insertion and extraction play a critical role in properly partitioning TA proteins despite limited and overlapping targeting information [28][29][30][31][32][33] . As representative TA proteins, BNIP3 and NIX are primarily localized to the OMM but have been demonstrated to localize to other membranes 34 .…”

Section: Introductionmentioning

confidence: 99%

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The ER membrane protein complex governs lysosomal turnover of a mitochondrial tail-anchored protein, BNIP3, to restrict mitophagy

Delgado

Shepard

Lamson

et al. 2023

Preprint

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Lysosomal degradation of autophagy receptors is a common proxy for selective autophagy. However, we find that two established mitophagy receptors, BNIP3 and BNIP3L/NIX, violate this assumption. Rather, BNIP3 and NIX are constitutively delivered to lysosomes in an autophagy-independent manner. This alternative lysosomal delivery of BNIP3 accounts for nearly all of its lysosome-mediated degradation, even upon mitophagy induction. To identify how BNIP3, a tail-anchored protein in the outer mitochondrial membrane, is delivered to lysosomes, we performed a genome-wide CRISPR screen for factors influencing BNIP3 flux. By this approach, we revealed both known modifiers of BNIP3 stability as well as a pronounced reliance on endolysosomal components, including the ER membrane protein complex (EMC). Importantly, the endolysosomal system regulates BNIP3 alongside, but independent of, the ubiquitin-proteosome system (UPS). Perturbation of either mechanism is sufficient to modulate BNIP3-associated mitophagy and affect underlying cellular physiology. In short, while BNIP3 can be cleared by parallel and partially compensatory quality control pathways, non-autophagic lysosomal degradation of BNIP3 is a strong post-translational modifier of BNIP3 function. More broadly, these data reveal an unanticipated connection between mitophagy and TA protein quality control, wherein the endolysosomal system provides a critical axis for regulating cellular metabolism. Moreover, these findings extend recent models for tail-anchored protein quality control and install endosomal trafficking and lysosomal degradation in the canon of pathways that ensure tight regulation of endogenous TA protein localization.

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“…In addition, a recently reported protein dislocation activity mediated by the ER-resident P5A-ATPase is required for the correct topogenesis of some Sec61 substrates ( McKenna et al. , 2020 ; McKenna et al. , 2022 ).…”

Section: Prospects For Studying Translocon Accessory Factorsmentioning

confidence: 99%

Protein biosynthesis at the ER: finding the right accessories

Shao

2023

MBoC

Self Cite

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More than 30% of eukaryotic proteins contain domains that must translocate across or integrate into the endoplasmic reticulum (ER) membrane. With few exceptions, protein translocation and transmembrane domain integration at the ER require the conserved Sec61 translocon. Decades of studies have established a clear mechanistic model for how the Sec61 translocon functions. The biosynthesis of distinct subsets of proteins at the ER also involves accessory factors that interact with the Sec61 translocon and translocating nascent proteins. However, assigning specific functions to many translocon accessory factors has been a persistent challenge in the field. This Perspective discusses recent insights into mechanisms that promote protein biosynthesis at the ER through accessory factors that directly regulate the Sec61 translocon or chaperone nascent proteins within the ER membrane. These translocon accessory factor functions, and more still to be discovered, are essential for producing a diverse and high-fidelity proteome at the ER.

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ATP13A1 prevents ERAD of folding-competent mislocalized and misoriented proteins

Cited by 21 publications

References 80 publications

A selectivity filter in the EMC limits protein mislocalization to the ER

A selectivity filter in the EMC limits protein mislocalization to the ER

The ER membrane protein complex governs lysosomal turnover of a mitochondrial tail-anchored protein, BNIP3, to restrict mitophagy

Protein biosynthesis at the ER: finding the right accessories

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