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OSTM1 is a ubiquitin E3 ligase that suppresses B-cell malignancy by activating the cAMP/PKA/CREB pathway

ABSTRACT: Osteoclastogenesis-associated transmembrane protein 1 (OSTM1) is a membrane-integral glycosylated protein that regulates lysosomal homeostasis and osteoclast maturation. Its loss-of-function mutations cause autosomal recessive osteopetrosis (ARO). In addition, OSTM1 was described as a putative ubiquitin E3 ligase yet with ill-defined substrates and biological functions. Using a whole-genome CRISPR/Cas9 screening in the interleukin-3 (IL3)-dependent Ba/F3 murine pro-B cell line, we identified OSTM1 whose silencing confers IL3-independent growth and in vivo transformation of Ba/F3 cells. In humans, OSTM1 is frequently deleted or downregulated across a wide range of B-cell malignancies. In mice, B-cell-specific monoallelic or biallelic ablation of Ostm1 cooperates with Cdkn2a ablation to drive lymphomagenesis with a near 100% penetrance. Mechanistically, a cytosolic, non-glycosylated fraction of OSTM1 acts as an E3 ligase that interacts with phosphodiesterase 3B (PDE3B) and promotes its proteasomal degradation. Because PDE3B catalyzes the conversion of cAMP to AMP and thereby negatively regulates the cAMP-dependent PKA/CREB/CREBBP tumor suppressive pathway, loss of OSTM1 leads to PDE3B stabilization and enhanced cell growth. Together, our findings uncover OSTM1 as a tumor-suppressive E3 ligase that promotes the proteasomal degradation of PDE3B and activates the cAMP-dependent PKA pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE338997 | GEO | 2026/09/23

REPOSITORIES: GEO

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OSTM1 is a tumor suppressor that restrains B-cell lymphomagenesis by promoting PDE3B degradation and activating cAMP-PKA-CREB signaling

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