Cytosolic aggregates in presence of nontranslocated proteins perturb endoplasmic reticulum structure and dynamics.

Debdatto Mookherjee, Priyanka Majumder, Rukmini Mukherjee, Debmita Chatterjee, Zenia Kaul, Subhrangshu Das, Rachid Sougrat, Saikat Chakrabarti, Oishee Chakrabarti

    Research output: Contribution to journalArticlepeer-review

    4 Scopus citations

    Abstract

    Presence of cytosolic protein aggregates and membrane damage are two common attributes of neurodegenerative diseases. These aggregates delay degradation of nontranslocated protein precursors leading to their persistence and accumulation in the cytosol. Here we find that cells with intracellular protein aggregates (of cytosolic prion protein or huntingtin) destabilise the endoplasmic reticulum (ER) morphology and dynamics when nontranslocated protein load is high. This affects trafficking of proteins out from the ER, relative distribution of the rough and smooth ER and three-way junctions that are essential for the structural integrity of the membrane network. The changes in ER membranes may be due to high aggregation tendency of the ER structural proteins - Reticulons, and altered distribution of those associated with the three-way ER junctions - Lunapark. Reticulon4 is seen to be enriched in the aggregate fractions in presence of nontranslocated protein precursors. This could be mitigated by improving signal sequence efficiencies of the proteins targeted to the ER. These were observed using PrP variants and the seven-pass transmembrane protein (CRFR1) with different signal sequences that led to diverse translocation efficiencies. This identifies a previously unappreciated consequence of cytosolic aggregates on nontranslocated precursor proteins - their persistent presence affects ER morphology and dynamics. This may be one of the ways in which cytosolic aggregates can affect endomembranes during neurodegenerative disease. This article is protected by copyright. All rights reserved.
    Original languageEnglish (US)
    Pages (from-to)943-960
    Number of pages18
    JournalTraffic (Copenhagen, Denmark)
    Volume20
    Issue number12
    DOIs
    StatePublished - Aug 31 2019

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