Unassembled CD147 is an endogenous endoplasmic reticulum-associated degradation substrate

Area of Science:

• Cell Biology
• Protein Degradation
• Molecular Mechanisms

Background:

• Endoplasmic reticulum-associated degradation (ERAD) removes misfolded proteins.
• The Hrd1 ubiquitin ligase, OS-9, SEL1L, and N-glycan recognition are key to ERAD.
• Existing ERAD knowledge relies heavily on overexpressed mutant proteins.

Purpose of the Study:

• To identify endogenous ERAD substrates.
• To investigate the role of the OS-9/SEL1L/Hrd1 pathway in degrading endogenous proteins.
• To characterize the degradation mechanism of CD147.

Main Methods:

• Mass spectrometry was used to identify ERAD substrates.
• SEL1L depletion was employed to observe substrate accumulation.
• Mutagenesis of lectin domains and treatment with kifunensine were utilized.

Main Results:

• Core-glycosylated CD147 (CD147(CG)) was identified as an endogenous ERAD substrate.
• CD147(CG) accumulates with OS-9 upon SEL1L depletion.
• The majority of CD147(CG) is degraded by the proteasome in a Hrd1-dependent manner.
• Kifunensine blocked CD147(CG) turnover, and lectin domain mutations inhibited OS-9/XTP3-B interaction.

Conclusions:

• Unassembled CD147(CG) is a constitutive substrate of the OS-9/SEL1L/Hrd1 ERAD pathway.
• This pathway plays a role in the degradation of essential assembly factors.
• The findings provide insights into endogenous protein quality control in the ER.