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Sci. Signal., 28 February 2012
Vol. 5, Issue 213, p. ec70
[DOI: 10.1126/scisignal.2002995]


Cell Death Death by Polyglutamine Tracts

Annalisa M. VanHook

Science Signaling, AAAS, Washington, DC 20005, USA

Protein domains rich in glutamine, such as those found in prion proteins, can form coiled-coil secondary structures that promote protein aggregation, and expansion of polyglutamine repeats is associated with several proteins that cause neurodegenerative disease. It has been proposed that proteins containing polyglutamine repeats play a normal role in inducing cell death and that expansion of these repeats in some proteins, such as huntingtin, induce aberrant cell death. Blum et al. report that a polyglutamine repeat–containing protein plays a role in a developmentally programmed cell death event in the nematode Caenorhabditis elegans. During development of the male reproductive tract in the fourth larval stage (L4), the linker cell, which is located at the distal tip of the gonad, undergoes cell death so that the gonad can connect to the cloaca. Linker cell death does not require caspases or other known apoptotic machinery and is characterized by morphological changes typical of necrotic cell death. In an RNA interference screen, the authors found that a protein isoform produced from the pqn-41 locus (PQN-41C) acted cell autonomously to promote death of the linker cell; however, knocking down pqn-41 prevented linker cell death in only 20% of animals. PQN-41C contains polyglutamine repeats that are predicted to form coiled coils, and green fluorescent protein–tagged PQN-41C formed cytoplasmic aggregates in the linker cell. Truncating the pairs of polyglutamine domains, which is predicted to disrupt the formation of coiled coils, abrogated the ability of transgenically expressed PQN-41C to rescue linker cell death in pqn-41 mutants. In contrast to other proteins containing polyglutamine repeats, overexpression of PQN-41C was not toxic, because it did not induce precocious linker cell death when expressed in male L2 larvae nor did it induce cell death when expressed in the gonad distal tip cells of hermaphrodites. Beginning in the embryo, pqn-41 was expressed in most cells but only activated in the linker cell shortly before its death. PQN-41C acted independently of the transcription factor LIN-29, a known regulator of linker cell death, but downstream of two proteins involved in innate immunity and the stress response—the Toll–interleukin 1 scaffolding protein TIR-1 and the mitogen-activated protein kinase kinase SEK-1. Given that PQN-41C cannot induce cell death on its own, it likely functions with other factors to induce this nonapoptotic form of developmentally programmed cell death. Linker cell death shares some morphological features with polyglutamine expansion diseases, suggesting that polyglutamine repeat–containing proteins may play a similar role in promoting nonapoptotic cell death in other species (see the Perspective by Link and Saldi).

E. S. Blum, M. C. Abraham, S. Yoshimura, Y. Lu, S. Shaham, Control of nonapoptotic developmental cell death in Caenorhabditis elegans by a polyglutamine-repeat protein. Science 335, 970–973 (2012). [Abstract] [Full Text]

C. D. Link, T. K. Saldi, Cell death by glutamine repeats? Science 335, 926–927 (2012). [Abstract] [Full Text]

Citation: A. M. VanHook, Death by Polyglutamine Tracts. Sci. Signal. 5, ec70 (2012).

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