The Yeast ER-Intramembrane Protease Ypf1 Refines Nutrient Sensing by Regulating Transporter Abundance

Avci, Dönem; Fuchs, Shai; Schrul, Bianca; Fukumori, Akio; Breker, Michal; Frumkin, Idan; Chen, Chia-yi; Biniossek, Martin L.; Kremmer, Elisabeth; Schilling, Oliver; Steiner, Harald; Schuldiner, Maya; Lemberg, Marius K.

doi:10.1016/j.molcel.2014.10.012

Cited by 50 publications

(60 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, we could visualize recruitment of Cdc48 to ER membrane foci upon clogger expression (Fig S6C). Dfm1 has recently been characterized to take part in the regulatory arm of ER associated degradation (ERAD-R) (Avci et al, 2014). However, the absence of another ERAD-R subunit, the protease Ypf1, does not affect clogging (Fig S6A and B), ruling out a general involvement of this pathway in unclogging.…”

Section: Resultsmentioning

confidence: 99%

The Protease Ste24 Clears Clogged Translocons

Ast

Michaelis

Schuldiner

2016

Cell

Self Cite

146

View full text Add to dashboard Cite

Summary Translocation into the endoplasmic reticulum (ER) is the first step in the biogenesis of thousands of eukaryotic endomembrane proteins. While functional ER translocation has been avidly studied, little is known about the quality control mechanisms that resolve faulty translocational states. One such faulty state is translocon clogging, in which the substrate fails to properly translocate and obstructs the translocon pore. To shed light on the machinery required to resolve clogging, we carried out a systematic screen in Saccharomyces cerevisiae that highlighted a role for the ER metalloprotease Ste24. We could demonstrate that Ste24 approaches the translocon upon clogging, interacts with and generates cleavage fragments of the clogged protein. Importantly, these functions are conserved in the human homologue, ZMPSTE24, while disease-associated mutant forms of ZMPSTE24 fail to clear the translocon. These results shed light on a new and critical task of Ste24, which safe-guards the essential process of translocation.

show abstract

Section: Resultsmentioning

confidence: 99%

The Protease Ste24 Clears Clogged Translocons

Ast

Michaelis

Schuldiner

2016

Cell

Self Cite

146

View full text Add to dashboard Cite

show abstract

“…The hexameric AAA+-type ATPase Cdc48 (known as p97 or VCP in mammals), and associated ubiquitin-binding proteins, are thought to provide the major driving force and directionality of these processes [37,44]. In a related manner, the second yeast derlin protein Dfm1 (for 'Der1-like family member 1') is a key component of several ERAD complexes, functionally interacting with either Hrd1, the second yeast ERAD E3 ubiquitin ligase Doa10 [45], or with the aspartyl intramembrane protease Ypf1 [37,46]. Interestingly, whereas Der1 is required for turnover of soluble ERAD substrates but is not essential for degradation of TM proteins [39,43,47,48], the few known Dfm1 clients are all membrane proteins [45,46] [43,45,49], suggesting that redundant degradation routes exist.…”

Section: Der1 Defines a Versatile Safeguard Of Er Protein Homeostasismentioning

confidence: 99%

Inactive rhomboid proteins: New mechanisms with implications in health and disease

Lemberg

Adrain

2016

Seminars in Cell & Developmental Biology

View full text Add to dashboard Cite

Rhomboids, proteases containing an unusual membrane-integral serine protease active site, were first identified in Drosophila, where they fulfill an essential role in epidermal growth factor receptor signaling, by cleaving membrane-tethered growth factor precursors. It has recently become apparent that eukaryotic genomes harbor conserved catalytically inactive rhomboid protease homologs, including derlins and iRhoms. Here we highlight how loss of proteolytic activity was followed in evolution by impressive functional diversification, enabling these pseudoproteases to fulfill crucial roles within the secretory pathway, including protein degradation, trafficking regulation, and inflammatory signaling. We distil the current understanding of the roles of rhomboid pseudoproteases in development and disease.

show abstract

“…The S. cerevisiae SPP Ypf1 is ER‐localized and is involved in degradation of the high‐affinity zinc transporter Zrt1. Zrt1 degradation by Ypf1 is dependent on nutrient sensing, which is regulated by the ERAD factors Dfm1 and Doa10, and this proteolytic process defines a noncanonical branch of the ERAD pathway called “ERAD regulatory” (Avci et al ., ).…”

Section: Introductionmentioning

confidence: 97%

The signal peptide peptidase SppA is involved in sterol regulatory element‐binding protein cleavage and hypoxia adaptation in Aspergillus nidulans

Bat-Ochir

Kwak

Koh

et al. 2016

Molecular Microbiology

View full text Add to dashboard Cite

Using forward genetics, we revealed that the signal peptide peptidase (SPP) SppA, an aspartyl protease involved in regulated intramembrane proteolysis (RIP), is essential for hypoxia adaptation in Aspergillus nidulans, as well as hypoxia-sensitive mutant alleles of a sterol regulatory element-binding protein (SREBP) srbA and the Dsc ubiquitin E3 ligase complex dscA-E. Both null and dead activity [D337A] mutants of sppA failed to grow in hypoxia, and the growth defect of ΔsppA was complemented by nuclear SrbA-N381 expression. Additionally, SppA interacted with SrbA in the endoplasmic reticulum, where SppA localized in normoxia and hypoxia. Expression of the truncated SrbA-N414 covering the SrbA sequence prior to the second transmembrane region rescued the growth of ΔdscA but not of ΔsppA in hypoxia. Unlike ΔdscA and ΔdscA;ΔsppA double mutants, in which SrbA cleavage was blocked, the molecular weight of cleaved SrbA increased in ΔsppA compared to the control strain in immunoblot analyses. Overall, our data demonstrate the sequential cleavage of SrbA by Dsc-linked proteolysis followed by SppA, proposing a new model of RIP for SREBP cleavage in fungal hypoxia adaptation. Furthermore, the function of SppA in hypoxia adaptation was consistent in Aspergillus fumigatus, suggesting the potential roles of SppA in fungal pathogenesis.

show abstract

The Yeast ER-Intramembrane Protease Ypf1 Refines Nutrient Sensing by Regulating Transporter Abundance

Cited by 50 publications

References 49 publications

The Protease Ste24 Clears Clogged Translocons

The Protease Ste24 Clears Clogged Translocons

Inactive rhomboid proteins: New mechanisms with implications in health and disease

The signal peptide peptidase SppA is involved in sterol regulatory element‐binding protein cleavage and hypoxia adaptation in Aspergillus nidulans

Contact Info

Product

Resources

About