LAMP5 modulates IRF4 stability and nuclear transport: a critical mechanism in myeloma progression and therapy.

Multiple myeloma is a malignant hematopoietic neoplasm characterized by unclear molecular mechanisms and lack of highly effective targeted therapies for clinical application. Interferon regulatory factor 4 (IRF4) is a well-known core transcription factor that regulates the progression of myeloma, but the molecular mechanisms underlying its protein homeostasis regulation are unknown. Our research shows that lysosomal-associated membrane protein 5 (LAMP5) interacts with IRF4 and prevents its degradation through the autophagy-lysosome pathway, thereby facilitating the progression of myeloma. Additionally, LAMP5 enhances the interaction between IRF4 and the nuclear transport protein karyopherin α2 (KPNA2), facilitating the nuclear transport of IRF4 and preventing its cytoplasmic retention and subsequent autophagy-lysosome degradation. Nuclear IRF4 promotes the transcription of c-MYC, and the c-MYC protein positively feeds back to activate LAMP5 transcription. This vicious regulatory loop drives rapid progression of myeloma. High-throughput drug screening shows pyrazofurin that significantly disrupts the interaction between LAMP5 and IRF4, leading to the degradation of IRF4 and inhibition of myeloma progression. This study elucidates a novel mechanism underlying IRF4 protein homeostasis maintenance and provides a potential inhibitor for myeloma treatment.