Fig. 4.

An updated view on TMEM106B biology and processing at the endolysosomal membrane. Prior to intramembrane proteolysis by SPPL2a, the C-terminal domain of TMEM106B may be released by canonical shedding through a lysosomal protease. Chang et al. proposed three novel candidate enzymes, which are indicated in the pink box. Conversely, Schweighauser et al. suggest that this region may not be accessible to lysosomal proteases. Instead, TMEM106B’s C-terminal domain may be released through non-canonical shedding. This may potentially also occur by SPPL2a, similar to non-canonical shedding of TNF-α [62]