A novel role for TMEM147 in cholesterol homeostasis

The highly conserved transmembrane protein TMEM147 has been shown to localise to the ER and be involved in stabilising membrane complexes, signalling and trafficking processes, but its exact function is unknown. In this study, Andri Christodoulou, Niovi Santama and co-workers (Christodoulou et al., 2020) now characterise the role of TMEM147 in HeLa cells. Using tagged versions of TMEM147, they show that TMEM147 also localises to the nuclear envelope (NE) in addition to the ER. Unexpectedly, siRNA-mediated silencing of TMEM147 results in a dramatic decrease in the levels of lamin B receptor (LBR), whereas other NE components are unaffected. This is accompanied by a mislocalisation of LBR to the ER, as well as chromatin decondensation and a change in nuclear shape. Furthermore, TMEM147 and LBR physically interact, and as shown here, this requires the C terminus of LBR, which has been shown to be important for cholesterol biogenesis. This prompted the authors to investigate the effect of TMEM147 knockout on other factors involved in cholesterol production. Indeed, they found that 7-dehydrocholesterol reductase (DHCR7), the enzyme catalysing the ultimate step in cholesterol synthesis, is also reduced, as are the overall cholesteryl ester levels in the cell, accompanied by changes in free cholesterol and increased cholesterol uptake. Finally, the authors show that TMEM147 also directly interacts with DHCR7, pointing to TMEM147 as a novel modulator of cholesterol homeostasis in the cell.