Immunity, 26 January, 2026, DOI：https://doi.org/10.1016/j.immuni.2025.12.009

Exosite-mediated targeting of GSDMB by dimeric granzyme A in lymphocyte pyroptotic killing

Xiu Zhong, Ya Su, Zhiwei Zhou, Yuqiu Sun, Yanjie Hou, Feng Shao, Jingjin Ding

Abstract

In cellular immunity, cytotoxic lymphocytes employ granzyme A (GZMA) to cleave and activate the pore-forming protein gasdermin B (GSDMB) for the pyroptotic killing of target cells. How GZMA recognizes and cleaves GSDMB is unknown. Here, we show that human GZMA targets GSDMB via specific, high-affinity binding to its autoinhibitory GSDMB-C domain. This binding requires the dimerization of GZMA, a unique property among human granzymes. A crystal structure of the GZMA-GSDMB-C complex shows a 2:2 stoichiometry, featuring an exosite at each of the two symmetric dimer interfaces in GZMA. The exosite engages a two-loop-organized site in the GSDMB-C domain, rendering a functional cleavage at Lys244 in GSDMB. Mouse GZMA (mGZMA) adopts a similar dimer structure, but its exosite is less efficient in engaging GSDMB. Mutation of the exosite enabled mGZMA to efficiently cleave and activate GSDMB. Our study reveals a substrate-targeting mechanism used by lymphocyte-derived granzymes to kill target cells.

Article link：https://www.cell.com/immunity/fulltext/S1074-7613(25)00565-5