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Published July 3, 2012 | Supplemental Material + Published
Journal Article Open

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments


In the course of apoptosis, activated caspases cleave ∼500 to ∼1,000 different proteins in a mammalian cell. The dynamics of apoptosis involve a number of previously identified, caspase-generated proapoptotic protein fragments, defined as those that increase the probability of apoptosis. In contrast to activated caspases, which can be counteracted by inhibitor of apoptosis proteins, there is little understanding of antiapoptotic responses to proapoptotic protein fragments. One possibility is the regulation of proapoptotic fragments through their selective degradation. The previously identified proapoptotic fragments Cys-RIPK1, Cys-TRAF1, Asp-BRCA1, Leu-LIMK1, Tyr-NEDD9, Arg-BID, Asp-BCL_XL, Arg-BIM_EL, Asp-EPHA4, and Tyr-MET bear destabilizing N-terminal residues. Tellingly, the destabilizing nature (but not necessarily the actual identity) of N-terminal residues of proapoptotic fragments was invariably conserved in evolution. Here, we show that these proapoptotic fragments are short-lived substrates of the Arg/N-end rule pathway. Metabolic stabilization of at least one such fragment, Cys-RIPK1, greatly augmented the activation of the apoptosis-inducing effector caspase-3. In agreement with this understanding, even a partial ablation of the Arg/N-end rule pathway in two specific N-end rule mutants is shown to sensitize cells to apoptosis. We also found that caspases can inactivate components of the Arg/N-end rule pathway, suggesting a mutual suppression between this pathway and proapoptotic signaling. Together, these results identify a mechanistically specific and functionally broad antiapoptotic role of the Arg/N-end rule pathway. In conjunction with other apoptosis-suppressing circuits, the Arg/N-end rule pathway contributes to thresholds that prevent a transient or otherwise weak proapoptotic signal from reaching the point of commitment to apoptosis.

Additional Information

© 2012 National Academy of Sciences. Contributed by Alexander Varshavsky, May 9, 2012 (sent for review April 25, 2012). Published online before print June 5, 2012. We thank B. Wadas for helpful comments on the manuscript, N. Malkova for advice and assistance with mouse experiments, J. Li for his contribution to producing anti-Ate1 antibody, and E. Udartseva for excellent technical assistance. We also thank the present and former members of the Varshavsky laboratory for their assistance and advice. This work was supported by National Institutes of Health Grants DK039520, GM031530, and GM085371 (to A.V.) and the March of Dimes Foundation. Author contributions: K.I.P., C.S.B., and A.V. designed research; K.I.P. and C.S.B. performed research; K.I.P., C.S.B., and A.V. analyzed data; and K.I.P., C.S.B., and A.V. wrote the paper. The authors declare no conflict of interest.

Attached Files

Published - Piatkov2012p19173P_Natl_Acad_Sci_Usa.pdf

Supplemental Material - pnas.201207786SI.pdf


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