A type 2 diabetes disease module with a high collective influence for Cdk2 and PTPLAD1 is localized in endosomes

Abstract

Despite the identification of many susceptibility genes our knowledge of the underlying mechanisms responsible for complex disease remains limited. Here, we identified a type 2 diabetes disease module in endosomes, and validate it for functional relevance on selected nodes. Using hepatic Golgi/endosomes fractions, we established a proteome of insulin receptor-containing endosomes that allowed the study of physical protein interaction networks on a type 2 diabetes background. The resulting collated network is formed by 313 nodes and 1147 edges with a topology organized around a few major hubs with Cdk2 displaying the highest collective influence. Overall, 88% of the nodes are associated with the type 2 diabetes genetic risk, including 101 new candidates. The Type 2 diabetes module is enriched with cytoskeleton and luminal acidification–dependent processes that are shared with secretion-related mechanisms. We identified new signaling pathways driven by Cdk2 and PTPLAD1 whose expression affects the association of the insulin receptor with TUBA, TUBB, the actin component ACTB and the endosomal sorting markers Rab5c and Rab11a. Therefore, the interactome of internalized insulin receptors reveals the presence of a type 2 diabetes disease module enriched in new layers of feedback loops required for insulin signaling, clearance and islet biology.

Network medicine-travelling with the insulin receptor: Encounter of the second type

“…2). Of interest, the T2D-protomodule functional specialization expands in IREN (to include cell cycle, trafficking, signaling components, reactive oxygen species components) [33]. “Hub bottlenicity” (also named centrality) is also thought to dictate essentiality and constitutes the dynamic component of a regulated network [34], [35].…”

“…Cdk2, which displays the highest centrality and is a high-confidence candidate associated with T2D genetic risk, indeed readily associates with key elements including the IR, PTPLAD1, Rab5c, tubulin and actin cytoskeletons all containing appropriate phosphorylation sites. In such a network, PTPLAD1, in the same incoherent input, controls IR tyrosine phosphorylation and other key interactions [33] (Fig. 2).…”

“…Amylin, a peptide which is co-secreted with insulin was, however, reported as a good substrate for IDE [56]. V-ATPase was found connected with ATIC and AMPK [33] and the widely used anti-diabetic drug metformin, targeting the mitochondrial production of ATP [51], was recently shown to act also on the endolysosomal system through V-ATPase and AMPK [57], [58], indicating the presence of connections between the T2D disease module and drug therapy. Additional layers of feedback loops are anticipated as a robust phosphorylation signal that was readily abolished by V-ATPase inhibition was reconstituted in endosomes, suggesting the presence of an endosomal homeostatic pathway, informing the cell that the lumenal acidification process is optimized [33].…”

“…This could only have occurred if the actual overnutrition state rarely or never appeared in the evolutionary history to not exert selective pressure against the use of unrelated signaling elements. Several evidence indicate the pathways identified in the T2D disease module belong to the first category as they are highly associated with the genetic disease risk [33]. Their evolutionary conservation is reminiscent, for example, of the integrated stress response (ISR), which is an organelle homeostatic response, that can be modulated by a small interactor (ISRIB) with the potential for future therapy of complex diseases [68], [69].…”

Insulin’s Discovery: New Insights on Its Hundredth Birthday: From Insulin Action and Clearance to Sweet Networks

“…In 2007, the first diseasome constructed by the mathematician Albert Barabasi from the Online Mendelian Inheritance in Man database (OMIM) showed that T2D occupies a central hub [21]. In 2018, the first T2D physical protein-protein interactions network (PPIN), constructed from validated variants, termed diabetes protomodule, displayed the proteins' hepatic nuclear factors HNF4A and HNF1A as central nodes [22] (Figure 2). The HNF1A variant identified by whole-exome sequencing in a homogeneous Latino cohort is an example of a rare variant with a high causality at a population level [23].…”