Substrate-specific translocational attenuation during ER stress defines a pre-emptive quality control pathway

Area of Science:

• Cell Biology
• Molecular Biology
• Protein Folding

Background:

• Eukaryotic proteins utilize signal sequences for translocation into the endoplasmic reticulum (ER).
• The diversity of these signal sequences has been observed but lacked functional explanation.
• ER stress can overwhelm protein folding capacity, leading to cellular dysfunction.

Purpose of the Study:

• To provide a functional rationale for signal sequence diversity in protein translocation.
• To investigate the role of signal sequences in modulating protein translocation during ER stress.
• To explore the concept of pre-emptive quality control (pQC) in the ER stress response.

Main Methods:

• Analysis of signal sequence function in protein translocation.
• Induction of acute and prolonged ER stress in cellular models.
• Assessment of protein rerouting to the cytosol for degradation.
• Evaluation of prion protein aggregation and cell viability under stress conditions.
• Pharmacological modulation of the pQC pathway.

Main Results:

• Signal sequence variations enable substrate-selective regulation of protein translocation.
• ER stress triggers a transient, signal-dependent attenuation of protein translocation.
• This attenuation reroutes proteins for cytosolic degradation, constituting a pre-emptive quality control (pQC) pathway.
• Bypassing pQC exacerbates prion protein aggregation and impairs cell recovery during prolonged stress.
• Enhancing pQC pharmacologically protects cells during ER stress.

Conclusions:

• Protein translocation is a regulated process exploited for pre-emptive quality control (pQC) during ER stress.
• Signal sequence diversity is crucial for substrate-selective pQC, mitigating ER proteotoxicity.
• Augmenting pQC represents a potential therapeutic strategy for ER-related diseases.