NatB-dependent acetylation protects procaspase-8 from UBR4-mediated degradation and is required for full induction of the extrinsic apoptosis pathway

Guedes, J. P.; Boyer, J. B.; Elurbide, J.; Carte, B.; Redeker, V.; Sago, L.; Meinnel, T.; Corte-Real, M.; Giglione, C.; Aldabe, R.

doi:10.1101/2023.09.25.559278

bioRxiv · 10.1101/2023.09.25.559278

NatB-dependent acetylation protects procaspase-8 from UBR4-mediated degradation and is required for full induction of the extrinsic apoptosis pathway

Guedes, J. P.·Boyer, J. B.·Elurbide, J.·Carte, B.·Redeker, V.·Sago, L.·Meinnel, T.·Corte-Real, M.·Giglione, C.·Aldabe, R.

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Abstract

N-terminal acetyltransferase B (NatB) is a major contributor to the N-terminal acetylome and is implicated in several key cellular processes including apoptosis and proteostasis. However, the molecular mechanisms linking NatB-mediated N-terminal acetylation to apoptosis and its relationship with protein homeostasis remain elusive. In this study, we generated mouse embryonic fibroblasts (MEFs) with an inactivated catalytic subunit of NatB (Naa20-/-) to investigate the impact of NatB deficiency on apoptosis regulation. Through quantitative N-terminomics, label-free quantification, and targeted proteomics, we demonstrated that NatB does not influence the proteostasis of all its substrates. Instead, our focus on putative NatB-dependent apoptotic factors revealed that NatB-mediated acetylation serves as a protective shield against UBR4 and UBR1 Arg/N-recognin-mediated degradation. Notably, Naa20-/- MEFs exhibited reduced responsiveness to extrinsic pro-apoptotic stimuli, a phenotype that was partially reversible upon UBR4 Arg/N-recognin silencing and consequent inhibition of procaspase-8 degradation. Collectively, our results shed light on how the interplay between NatB-mediated acetylation and the Arg/N-degron pathway impacts apoptosis regulation, providing new perspectives in the field including in therapeutic interventions.

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Guedes, J. P., Boyer, J. B., Elurbide, J., Carte, B., Redeker, V., Sago, L., Meinnel, T., Corte-Real, M., Giglione, C., Aldabe, R.. 2023-09-25. NatB-dependent acetylation protects procaspase-8 from UBR4-mediated degradation and is required for full induction of the extrinsic apoptosis pathway. https://doi.org/10.1101/2023.09.25.559278

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