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

Tariq, M. U.; Sheshadri, N.; Shen, J.; Jung, J.; Li, R.; Lu, K.; Yan, J.; Koch, M. C.; Caso, G.; Sajjad, H.; Vallat, B.; Burley, S. K.; Sun, Y.; Liu, T.; Li, H.; Hinrichs, C.; Bertoni, F.; Lin, R. Z.; Wang, J.; Wang, L. Y.; Vacher, J.; Xie, P.; Zong, W.-X.

doi:10.64898/2026.01.23.701155

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bioRxiv · 10.64898/2026.01.23.701155

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

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Abstract

Osteoclastogenesis-associated transmembrane protein 1 (OSTM1) is a glycosylated, membrane-integral protein that regulates lysosomal homeostasis, with loss-of-function mutations causing autosomal recessive osteopetrosis. Through a whole-genome CRISPR/Cas9 screen, we identified OSTM1 as a previously unrecognized tumor suppressor in B-cell malignancies. Consistent with this role, OSTM1 is frequently deleted or downregulated across a broad spectrum of human B-cell cancers. In mice, B-cell-specific monoallelic or biallelic ablation of Ostm1 cooperates with Cdkn2a loss to drive lymphomagenesis with near-complete penetrance. Mechanistically, we uncover a cytosolic, non-glycosylated fraction of OSTM1 that functions as a ubiquitin E3 ligase to promote proteasomal degradation of phosphodiesterase 3B (PDE3B). As PDE3B hydrolyzes cAMP and suppresses the tumor-protective PKA/CREB/CREBBP signaling axis, loss of OSTM1 leads to PDE3B stabilization, attenuation of cAMP signaling, and enhanced oncogenic transformation. Together, our findings establish OSTM1 as a critical suppressor of B-cell lymphomagenesis through regulation of the cAMP/PKA/CREB pathway.

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Tariq, M. U., Sheshadri, N., Shen, J., Jung, J., Li, R., Lu, K., Yan, J., Koch, M. C., Caso, G., Sajjad, H., Vallat, B., Burley, S. K., Sun, Y., Liu, T., Li, H., Hinrichs, C., Bertoni, F., Lin, R. Z., Wang, J., Wang, L. Y., Vacher, J., Xie, P., Zong, W.-X.. 2026-01-26. OSTM1 is a ubiquitin E3 ligase that suppresses B-cell malignancy by activating the cAMP/PKA/CREB pathway. https://doi.org/10.64898/2026.01.23.701155

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