😉

When I was a sailor 😀

We identified inceptor as clathrin-coated membrane associated TGN proinsulin and insulin lysosomal sorting and degradation receptor. We are now exploiting these findings in the context of beta cell physiology and regeneration.

Previously, we could show that an adaptor protein binding motif is essential for AP2 binding and efficient clathrin-mediated endocytosis from the PM (Ansarullah et al., 2021; Nature). Now we show that inceptor binds to AP1/3 which are essential for CCV budding from the TGN.

Of note, inceptor has a mannose-6-phosphate domain and a lysosomal targeting motif in its cytoplasmic domain. On the subcellular level inceptor mainly localizes to the trans-Golgi network (TGN) and clathrin-coated vesicles (CCVs) and late end/lysosome.

The increased proinsulin and insulin content also translates into improved 1st and 2nd phase glucose stimulated insulin secretion of the KO SC-beta cells, when compared to WT SC-beta cells.

Strikingly, both WT (+/+) and KO (IIR-/-) C-pep-Cherry reporter iPSC show similar SC-beta cell differentiation efficiency (day 20), but inceptor KO SC-beta cells show better survival in vitro and a massively increased proinsulin & insulin content in extended S6 cultures (day 40).

Johanna then used the iPSC WT and KO iPSC lines for stem cell (SC)-derived islet/beta cell differentiation. Interestingly, inceptor is highly upregulated when insulin-producing beta cells are born after endocrine induction at stage (S) 5 and 6.