Sec61 complex/translocon: The role of an atypical ER Ca2+-leak channel in health and disease

Abstract

The heterotrimeric Sec61 protein complex forms the functional core of the so-called translocon that forms an aqueous channel in the endoplasmic reticulum (ER). The primary role of the Sec61 complex is to allow protein import in the ER during translation. Surprisingly, a completely different function in intracellular Ca2+ homeostasis has emerged for the Sec61 complex, and the latter is now accepted as one of the major Ca2+-leak pathways of the ER. In this review, we first discuss the structure of the Sec61 complex and focus on the pharmacology and regulation of the Sec61 complex as a Ca2+-leak channel. Subsequently, we will pay particular attention to pathologies that are linked to Sec61 mutations, such as plasma cell deficiency and congenital neutropenia. Finally, we will explore the relevance of the Sec61 complex as a Ca2+-leak channel in various pathophysiological (ER stress, apoptosis, ischemia-reperfusion) and pathological (type 2 diabetes, cancer) settings.

Kinetics of the thapsigargin-induced Ca2+ mobilisation: A quantitative analysis in the HEK-293 cell line

“…Several studies have analysed the action of pharmacological active substances on the ER Ca 2+ leak mediated by Sec61 translocons mostly by measuring the effects of these substances on TG-induced cytosolic Ca 2+ transients (see Parys and van Coppenolle, 2022 ). Seminal work with tunicamycin, dithiothreitol (DTT), trifluoperazine and ophiobolin A has shown that these substances enhance TG-induced cytosolic Ca 2+ transients by increasing specifically the Ca 2+ leak through Sec61 translocons ( Erdmann et al, 2011 ; Schäuble et al, 2012 ).…”

“…Most studies of the Ca 2+ leak from ER have been performed in the absence of external Ca 2+ to avoid SOCE (see Lomax et al, 2002 ; Lang et al, 2017 ; Parys and van Coppenolle, 2022 ). In this approach, the Ca 2+ leak from ER is the only Ca 2+ source underlying changes in [Ca 2+ ] cyt .…”

“…Several studies have identified the Sec61 translocon as a Ca 2+ leak channel in the ER, which is tightly controlled by BiP and Ca 2+ -calmodulin ( Lang et al, 2017 ). Other ion channels such as ORAI3, TRPC1, and BI-1 have been also reported to mediate Ca 2+ leak from the ER, aside from the evoked Ca 2+ release through IP 3 and ryanodine receptors ( Camello et al, 2002 ; Lemos et al, 2021 ; Parys and van Coppenolle, 2022 ). Therefore, it is not surprising that thapsigargin (TG) became a popular substance used experimentally to induce ER Ca 2+ depletion.…”

SEC61 translocon subunit gamma enhances low-dose cisplatin-induced cancer-stem cell properties of head and neck squamous cell carcinoma via enhancing Ca2+-mediated autophagy

“…Besides the role as a translocon channel, SEC61 complexes is also a ubiquitous major ER Ca 2+ leak channel, regulating calcium leakage from the ER into the cytosol. 11 , 28 The ER is the largest intracellular Ca 2+ reservoir. Therefore, Ca 2+ ions released from the ER may alter a series of intracellular Ca 2+ signaling pathways.…”

“…Therefore, Ca 2+ ions released from the ER may alter a series of intracellular Ca 2+ signaling pathways. 28 Intracellular Ca 2+ plays a crucial role in basal and induced autophagy. 19 Increased cytosolic Ca 2+ can induce autophagy through multiple pathways, such as Ca 2+ /calmodulin-dependent kinase kinase (CaMKKβ), Ca 2+ /protein kinase C, Ca 2+ /ERK and Ca 2+ /Vps34 (a calmodulin-binding protein).…”