Derlin Dfm1 Employs a Chaperone Function to Resolve Misfolded Membrane Protein Stress

Kandel, Rachel; Jung, Jasmine; Dysau, Della; Kuo, Tiffany; Songster, Livia D; Aguayo, Analine; Duttke, Sascha H.; Benner, Chris; Neal, Sonya E.

doi:10.1101/2022.01.25.477788

Cited by 2 publications

(2 citation statements)

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“…Instead, Dfm1 interacts with Ypk1‐dependent phosphorylated Orm2, which is followed by Orm2 exit from the ER and degradation by EGAD. Our laboratory has recently identified a chaperone‐like Dfm1 function where it influences the solubility of aggregate‐prone misfolded membrane substrates along the ER membrane (preprint: Kandel et al , 2022 ). Similar to Dfm1's function as a mediator in sphingolipid homeostasis, its chaperone‐like role requires Dfm1's substrate‐binding and lipid‐thinning function, but not its Cdc48 recruitment function.…”

Section: Discussionmentioning

confidence: 99%

An ERAD‐independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis

et al. 2022

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Nearly one-third of nascent proteins are initially targeted to the endoplasmic reticulum (ER), where they are correctly folded and assembled before being delivered to their final cellular destinations. To prevent the accumulation of misfolded membrane proteins, ERassociated degradation (ERAD) removes these client proteins from the ER membrane to the cytosol in a process known as retrotranslocation. Our previous work demonstrated that rhomboid pseudoprotease Dfm1 is involved in the retrotranslocation of ubiquitinated membrane integral ERAD substrates. Herein, we found that Dfm1 associates with the SPOTS complex, which is composed of serine palmitoyltransferase (SPT) enzymes and accessory components that are critical for catalyzing the first rate-limiting step of the sphingolipid biosynthesis pathway. Furthermore, Dfm1 employs an ERADindependent role for facilitating the ER export and endosome-and Golgi-associated degradation (EGAD) of Orm2, which is a major antagonist of SPT activity. Given that the accumulation of human Orm2 homologs, ORMDLs, is associated with various pathologies, our study serves as a molecular foothold for understanding how dysregulation of sphingolipid metabolism leads to various diseases.

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Section: Discussionmentioning

confidence: 99%

An ERAD‐independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis

et al. 2022

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“…However, we cannot exclude the possibility that Dfm1 may directly participate in Orm2 export in a COPII-independent manner. The former model seems plausible since our laboratory has recently identified a chaperone-like Dfm1 function that is required for disaggregating misfolded membrane substrates along the ER membrane (Kandel et al, 2022). Similar to Dfm1’s function as a mediator in sphingolipid homeostasis, its chaperone-like role requires Dfm1’s substrate and lipid thinning function, but not its Cdc48 recruitment function.…”

Section: Discussionmentioning

confidence: 99%

An ERAD-independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis

Bhaduri

Aguayo

Ohno

et al. 2022

Preprint

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Nearly one-third of nascent proteins are initially targeted to the endoplasmic reticulum (ER) where they are correctly folded and assembled before being delivered to their final cellular destinations. To prevent the accumulation of misfolded membrane proteins ER-associated-degradation (ERAD) removes these clients from the ER membrane to the cytosol in a process known as retrotranslocation. Our recent work demonstrates that rhomboid pseudoprotease Dfm1 is involved in the retrotranslocation of ubiquitinated integral membrane ERAD substrates. To survey for potential interaction partners of Dfm1 we performed protein-proximity labeling by BioID (proximity-dependent biotin identification) followed by mass spectrometry and identified several interacting proteins known to play a role in the sphingolipid biosynthesis pathway. Specifically we found that Dfm1 physically interacts with the SPOTS complex which is composed of serine palmitoyltransferase (SPT) enzymes and accessory components and is critical for catalyzing the first rate-limiting step of the sphingolipid biosynthesis pathway. We demonstrate for the first time that Dfm1 has a role in ER export a function that is independent of Dfm1s canonical ERAD retrotranslocation function. Specifically we show that loss of Dfm1 results in the accumulation of phosphorylated Orm2 at the ER suggesting a novel role for Dfm1 in controlling Orm2 export from the ER and its subsequent degradation by EGAD. Moreover recruitment of Cdc48 by Dfm1 which is critical for its role in ERAD retrotranslocation is dispensable for Dfm1s role in ER export. Given that the accumulation of human Orm2 homologs ORMDLs are associated with many maladies our study serves as a molecular foothold for understanding how dysregulation of sphingolipid metabolism leads to various diseases.

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Derlin Dfm1 Employs a Chaperone Function to Resolve Misfolded Membrane Protein Stress

Cited by 2 publications

References 60 publications

An ERAD‐independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis

An ERAD‐independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis

An ERAD-independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis

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