Lipid droplets as flexible substrates for protein phase separation

Kamatar, Advika; Stachowiak, Jeanne C.; Parekh, Sapun H.

doi:10.1016/j.bpj.2022.11.533

Cited by 1 publication

(1 citation statement)

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“…Aggresomes like phase-separated granules are often formed due to the condensation of proteins triggered by changes in lipid metabolism [36]. Recent reports have suggested lipid droplets serve as a substrate for protein phase separation of intrinsically disordered proteins [37]. A systems genetics study by Parker et al [15] reported that PSMD9 regulates levels of several lipid species in mouse liver.…”

Section: Psmd9 Regulates the Abundance Of Lipid Dropletsmentioning

confidence: 99%

The interaction network of the proteasome assembly chaperone PSMD9 regulates proteostasis

Christie,

Anthony,

Harish

et al. 2023

The FEBS Journal

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Functional networks in cells are created by physical, genetic, and regulatory interactions. Mapping them and annotating their functions by available methods remains a challenge. We use affinity purification mass spectrometry (AP‐MS) coupled with SLiMFinder to discern such a network involving 26S proteasome non‐ATPase regulatory subunit 9 (PSMD9), a chaperone of proteasome assembly. Approximately 20% of proteins within the PSMD9 interactome carry a short linear motif (SLiM) of the type ‘EXKK’. The binding of purified PSMD9 with the peptide sequence ERKK, proteins heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNPA2B1; containing ERKK), and peroxiredoxin‐6 (PRDX6; containing EAKK) provided proof of principle for this motif‐driven network. The EXKK motif in the peptide primarily interacts with the coiled‐coil N domain of PSMD9, a unique interaction not reported for any coiled‐coil domain. PSMD9 knockout (KO) HEK293 cells experience endoplasmic reticulum (ER) stress and respond by increasing the unfolded protein response (UPR) and reducing the formation of aggresomes and lipid droplets. Trans‐expression of PSMD9 in the KO cells rescues lipid droplet formation. Overexpression of PSMD9 in HEK293 cells results in reduced UPR, and increased lipid droplet and aggresome formation. The outcome argues for the prominent role of PSMD9 in maintaining proteostasis. Probable mechanisms involve the binding of PSMD9 to binding immunoglobulin protein (BIP/GRP78; containing EDKK), an endoplasmic reticulum chaperone and key regulator of the UPR, and fatty acid synthase (FASN; containing ELKK), involved in fatty acid synthesis/lipid biogenesis. We propose that PSMD9 acts as a buffer in the cellular milieu by moderating the UPR and enhancing aggresome formation to reduce stress‐induced proteotoxicity. Akin to waves created in ponds that perpetuate to a distance, perturbing the levels of PSMD9 would cause ripples down the networks, affecting final reactions in the pathway, one of which is altered proteostasis.

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Section: Psmd9 Regulates the Abundance Of Lipid Dropletsmentioning

confidence: 99%