All human granzymes target hnRNP K that is essential for tumor cell viability.

The Journal of Biological Chemistry
R van DomselaarNiels Bovenschen

Abstract

Granule exocytosis by cytotoxic lymphocytes is the key mechanism to eliminate virus-infected cells and tumor cells. These lytic granules contain the pore-forming protein perforin and a set of five serine proteases called granzymes. All human granzymes display distinct substrate specificities and induce cell death by cleaving critical intracellular death substrates. In the present study, we show that all human granzymes directly cleaved the DNA/RNA-binding protein heterogeneous nuclear ribonucleoprotein K (hnRNP K), designating hnRNP K as the first known pan-granzyme substrate. Cleavage of hnRNP K was more efficient in the presence of RNA and occurred in two apparent proteolysis-sensitive amino acid regions, thereby dissecting the functional DNA/RNA-binding hnRNP K domains. HnRNP K was cleaved under physiological conditions when purified granzymes were delivered into living tumor cells and during lymphokine-activated killer cell-mediated attack. HnRNP K is essential for tumor cell viability, since knockdown of hnRNP K resulted in spontaneous tumor cell apoptosis with caspase activation and reactive oxygen species production. This apoptosis was more pronounced at low tumor cell density where hnRNP K knockdown also triggered a cas...Continue Reading

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Citations

Nov 5, 2013·Cell Death and Differentiation·S A H de PootN Bovenschen
Jan 15, 2014·Cell Death and Differentiation·S A H de Poot, N Bovenschen
Feb 12, 2014·Journal of Cancer Research and Therapeutics·Na HanMengxian Zhang
Jan 29, 2016·Molecular & Cellular Proteomics : MCP·Emilie Bigaud, Fernando J Corrales
May 23, 2015·Nature Reviews. Immunology·Ilia VoskoboinikJoseph A Trapani
Sep 16, 2020·Journal of Leukocyte Biology·Claudia CantoniMassimo Vitale
Apr 29, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Marshall P ThomasJudy Lieberman
May 22, 2021·Frontiers in Immunology·Annemieke C BouwmanNiels Bovenschen
Sep 17, 2021·PLoS Pathogens·Lisanne C de JongNiels Bovenschen
Oct 19, 2021·Frontiers in Immunology·Andrew SnyderJennifer A Muszynski

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