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A conformation-dependent hydrophobic degron determines Rab9a-mediated vesicular trafficking
Jun Shirai1, Toshiki Takahashi1, Hiroyuki Kawahara1
1Department of Biological Sciences, Laboratory of Cell Biology and Biochemistry, Tokyo Metropolitan University, Tokyo, Japan.
The Journal of Biological Chemistry
|February 2, 2026
Summary
The protein quality control (PQC) machinery targets GDP-bound Rab9 for degradation via a conformation-dependent hydrophobic (CDH) degron. This PQC pathway is essential for proper mannose-6-phosphate receptor trafficking.
Area of Science:
- Cell Biology
- Molecular Biology
- Protein Degradation
Background:
- Rab9 GTPase is crucial for mannose-6-phosphate receptor (CI-M6PR) vesicular trafficking.
- Protein quality control (PQC) dysfunction impacts CI-M6PR trafficking, but the underlying mechanisms are unclear.
Purpose of the Study:
- To elucidate the mechanism by which PQC machinery influences CI-M6PR trafficking via Rab9.
- To identify the specific features of Rab9 recognized by the PQC system.
Main Methods:
- Comparative amino acid sequence analysis of Rab9 and Rab7.
- Investigation of Rab9 half-life and stability.
- Functional assays using mutated Rab9 proteins.
- Identification of PQC factors involved in Rab9 regulation.
Main Results:
- GDP-bound Rab9 exhibits an extremely short half-life compared to Rab7.
- Exposed hydrophobic residues in Rab9's Switch I region form a conformation-dependent hydrophobic (CDH) degron.
- The CDH degron targets Rab9 for PQC-mediated degradation.
- Mutations disrupting the CDH degron lead to Rab9 accumulation and defective CI-M6PR localization.
- VCP/p97 was identified as a key PQC factor for GDP-bound Rab9.
Conclusions:
- The CDH degron is a novel regulatory element conferring instability to Rab9.
- CDH degron-mediated PQC is essential for maintaining Rab9 function and proper CI-M6PR trafficking.
- VCP/p97 is a critical component of the PQC pathway regulating Rab9 stability.
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