SEC61: a potential therapeutic target in transplantation

The SEC61 translocon complex has emerged as a multifunctional therapeutic target linking protein secretion, calcium homeostasis, and immune regulation in kidney transplantation. Beyond canonical protein translocation, SEC61 regulates antigen cross-presentation, cytokine secretion (IL-2, IFN-γ, TNF-α), surface activation molecules (CD62L), and functions as an endoplasmic reticulum calcium-leak channel that modulates unfolded protein response activation under specific physiological and stress conditions. During ischemia-reperfusion injury, ATP depletion impairs SERCA-mediated calcium reuptake while SEC61-mediated calcium efflux persists, triggering ER stress and tubular injury. Selective pharmacological SEC61 inhibition has been proposed to confer multiple immunomodulatory and cytoprotective effects - including reduced antigen cross-presentation, suppression of high-burden secretory lymphocytes, limited T cell migration, and intrinsic antiviral activity through blockade of envelope glycoprotein biogenesis-based on mechanistic and preclinical evidence, although these effects remain to be validated in transplant-specific models. Emerging phase I oncology data with client-selective inhibitors demonstrate the feasibility of pharmacologic SEC61 modulation in humans, although the safety, dosing, and patient population in transplantation may differ substantially from oncology settings. This review examines SEC61's multifaceted roles in transplant immunobiology and its therapeutic potential as a novel immunomodulatory target in kidney transplantation.