Abstract A035: ER-associated retrotranslocation generates a cytosolic OSTM1 E3 ubiquitin ligase that targets PDE3B for degradation

Abstract

Osteoclastogenesis-associated transmembrane protein 1 (OSTM1) is an ER/lysosomal luminal glycoprotein essential for lysosomal homeostasis, and its loss-of-function causes autosomal recessive osteopetrosis. We recently identified OSTM1 as a tumor suppressor in B-cell lymphomas (BCL) by promoting proteasomal degradation of phosphodiesterase 3B (PDE3B), but how a luminal protein exerts E3 ubiquitin ligase activity has remained unresolved. Here, we show that OSTM1 undergoes endoplasmic reticulum (ER)-associated retrotranslocation to generate a non-glycosylated cytosolic species, which preferentially engages PDE3B and catalyzes its ubiquitination and proteasomal turnover. Functionally, while the non-glycosylated cytosolic pool of OSTM1 predominantly exists in primary hematological cells, OSTM1 loss leads to PDE3B accumulation, enhanced cAMP hydrolysis, and attenuation of the tumor-suppressive PKA/CREB signaling axis. Genetic or pharmacological inhibition of PDE3B limits tumor growth and sensitizes cells to PI3Kγ inhibition. These findings establish glycosylation-dependent subcellular localization OSTM1 as a key determinant of its E3 activity and tumor-suppressive function and reveal PDE3B signaling as a therapeutic vulnerability in B-cell lymphoma.