NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Multiple myeloma (MM) is an incurable plasma cell malignancy.
• Understanding drug sensitivity mechanisms in MM is crucial for effective treatment.
• The role of E3 ligases in MM drug response is an active area of research.

Purpose of the Study:

• To investigate the role of neural precursor cell-expressed developmentally downregulated gene 4L (NEDD4L) in regulating drug sensitivity in multiple myeloma.
• To elucidate the molecular mechanisms by which NEDD4L influences MM cell response to bortezomib.
• To evaluate NEDD4L as a potential biomarker and therapeutic target in MM.

Main Methods:

• Investigated the interaction between NEDD4L and the 19S proteasome.
• Assessed the impact of NEDD4L suppression on bortezomib sensitivity in vitro and in vivo.
• Analyzed the role of autophagy in mediating NEDD4L's effect on drug sensitivity.
• Correlated NEDD4L expression levels with clinical response to bortezomib.

Main Results:

• NEDD4L, a HECT E3 ligase, binds the 19S proteasome, inhibiting its proteolytic activity and enhancing autophagy.
• Suppression of NEDD4L reduced bortezomib sensitivity by inhibiting autophagy, an effect reversed by autophagy activators.
• Elevated NEDD4L expression in patients correlated with increased response rates, longer duration of response, and improved overall prognosis to bortezomib therapy.

Conclusions:

• NEDD4L plays a critical role in modulating bortezomib sensitivity in multiple myeloma through autophagy regulation.
• NEDD4L serves as a promising predictive biomarker for identifying patients likely to benefit from bortezomib.
• Targeting NEDD4L represents a novel therapeutic strategy for enhancing bortezomib efficacy in multiple myeloma.