The prion protein is embedded in a molecular environment that modulates transforming growth factor β and integrin signaling

Abstract

At times, it can be difficult to discern if a lack of overlap in reported interactions for a protein-of-interest reflects differences in methodology or biology. In such instances, systematic analyses of protein-protein networks across diverse paradigms can provide valuable insights. Here, we interrogated the interactome of the prion protein (PrP), best known for its central role in prion diseases, in four mouse cell lines. Analyses made use of identical affinity capture and sample processing workflows. Negative controls were generated from PrP knockout lines of the respective cell models, and the relative levels of peptides were quantified using isobaric labels. The study uncovered 26 proteins that reside in proximity to PrP. All of these proteins are predicted to have access to the outer face of the plasma membrane, and approximately half of them were not reported to interact with PrP before. Strikingly, although several proteins exhibited profound co-enrichment with PrP in a given model, except for the neural cell adhesion molecule 1, no protein was highly enriched in all PrP-specific interactomes. However, Gene Ontology analyses revealed a shared association of the majority of PrP candidate interactors with cellular events at the intersection of transforming growth factor β and integrin signaling.

Tau interactome analyses in CRISPR-Cas9 engineered neuronal cells reveal ATPase-dependent binding of wild-type but not P301L Tau to non-muscle myosins

“…Surprisingly, the current study documented DJ-1 to be preferentially associated with P301L mutant Tau or wild-type Tau in IMR or ReN cells, respectively. This finding serves as yet another data point in an emerging body of literature that cautions against the expectation that protein-protein interactions are mostly conserved when comparisons are made across paradigms 32 . A battery of tests that explored if these observations reflected (1) cell type-specific differences in steady-state expression levels of DJ-1, (2) differences in the cells’ ability to deploy DJ-1 as a scavenger of reactive oxygens, or (3) broader differences in the cells’ coping with redox stress, has to this date not yielded a clue for interpreting this finding (Fig.…”

Prion protein modulates endothelial to mesenchyme-like transition in trabecular meshwork cells: Implications for primary open angle glaucoma

“…It is remarkable that downregulation of PrP C in TM cells caused significant upregulation of several fibrillogenic proteins including α-SMA, fibronectin, and collagen 1A, suggesting transformation to a mesenchyme-like phenotype 11,13,38,58 . Absence of PrP C in neuronal cells induces aggregation of β1-integrin on the plasma membrane, activating signaling pathways including RhoA-ROCK that interfere with neuronal polarity and axonal growth by altering cell-ECM interactions 5–8,26,59,60 . Our data suggest that a similar mechanism operates in TM cells, and induces upregulation of fibrillogenic proteins typical of the glaucomatous change 12,15 .…”

“…Examples include signaling through integrins 19–21 , TGFβ2 21,22 , autotaxin-LPA 23 , JNK-paxillin 24 , and cross-talk between TGFβ, integrins, and the ECM 25 to name a few. An additional possible player is PrP C , a documented inducer of EMT through β1-integrin and RhoA-ROCK activation 5,7,11,26 . This question deserves attention because PrP C is cleaved by members of the disintegrin and matrix-metalloprotease family of enzymes that are upregulated in the aqueous humor (AH) of glaucomatous eyes 27,28 , and is likely to confound the pathogenesis and therapeutic management of POAG through cross-talk with other pathways 29 .…”

The Prion-like protein Shadoo is involved in mouse embryonic and mammary development and differentiation

“…Some pathways identified above are reminiscent of those described for PrP modulation of EMT 18,19 . PrP regulates embryonic stem cell pluripotency and differentiation, and Shadoo and PrP share biological properties 9 although recent experiments suggest that it could depend of the model system used 20,21 .…”