Here we will review the functions of INSIG1 and SCAP in the regulatory hub that determine SREBP activity and synthesis of cholesterol and fatty acids vs STING activity and signaling in the innate immunity pathway that also signals to TBK1, a protein that is mutated in amyotrophic lateral sclerosis (ALS) (Freischmidt et al., 2017). Here, INSIG1 is linked to amyotrophic lateral sclerosis.