Autoadaptive ER-associated degradation defines a preemptive unfolded protein response pathway

Area of Science:

• Cellular Biology
• Molecular Biology
• Biochemistry

Background:

• Efficient clearance of misfolded proteins from the endoplasmic reticulum (ER) is crucial for maintaining cellular proteostasis.
• Misfolded proteins are targeted for degradation via ER-associated degradation (ERAD) pathways involving dislocation machineries (dislocons) and E3 ubiquitin ligases.

Purpose of the Study:

• To investigate the intrinsic stability of the HRD1 dislocon and the turnover of its scaffold protein, HERP.
• To elucidate the regulatory mechanisms governing ERAD activity in response to misfolded protein load.

Main Methods:

• Analysis of HRD1 dislocon stability and HERP protein turnover.
• Investigation of the role of HRD1 clients in regulating the HERP degradation pathway.
• Characterization of the UBC6e/RNF5/p97/proteasome-controlled relay.

Main Results:

• The HRD1 dislocon exhibits intrinsic instability, with rapid turnover of the scaffold protein HERP.
• HRD1 dislocon integrity is maintained by HRD1 clients, which modulate HERP turnover in a dose-dependent manner.
• HRD1 clients interrupt the UBC6e/RNF5/p97/proteasome pathway controlling HERP degradation.

Conclusions:

• ER-associated degradation (ERAD) employs autoadaptive regulatory pathways, termed ERAD tuning.
• ERAD tuning allows rapid adaptation of degradation activity to misfolded protein levels.
• This adaptive mechanism helps to prevent the activation of the unfolded protein response (UPR).