Updated project metadata. Plants respond to mechanical stressors in a variety of ways, producing electrical and biochemical signals, altering gene expression profiles, and changing organellar organization and morphology. We used a combination of genetic and proteomic approaches to identify genes that modify signaling of MSL10, a mechanosensitive ion channel in Arabidopsis which promotes programmed cell death in response to the mechanical stress from osmotic cell swelling. Mass spectrometry was used to identify proteins that co-immunoprecipitate with MSL10-GFP or with MSL107xD-GFP, a phosphomimetic variant that cannot activate cell death signaling. Interestingly, proteomics identified many proteins that are found at ER-plasma membrane contact sites (EPCSs). Two of the most abundant proteins that co-precipitated with MSL10 are the EPCS proteins VAP27-1 and SYT1, both of which have been reported to relocalize into spherical membrane structures in response to mechanical stress, a phenomenon also observed with MSL10. SYT1 has previously been shown to promote resistance to mechanical stress. A suppressor screen of the gain-of-function msl10-3G allele yielded mutants with point mutations in synaptotagmin (SYT)5 and SYT7, proteins that form a functional complex with SYT1. Together, these results suggest that MSL10 interacts with SYT1, SYT5, and SYT7 at EPCSs and that its cell death signaling output is modulated by this interaction.