The multiple functions of the co-chaperone stress inducible protein 1

Fonseca, Anna Carolina Carvalho da; Matias, Diana; Geraldo, Luiz Henrique Medeiros; Leser, Felipe Saceanu; Pagnoncelli, Iohana; García, Celina; Amaral, Rackele Ferreira do; Rosa, Bárbara Gomes da; Grimaldi, Izabella; Magalhães, Eduardo Sabino de Camargo; Cóppola-Segovia, Valentín; Azevedo, Evellyn M.; Zanata, Sı́lvio M.; Lima, Flávia Regina Souza

doi:10.1016/j.cytogfr.2020.06.003

Cited by 15 publications

(12 citation statements)

References 105 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5). Based on this model and our own corroborating literature review, STI1 (encoded by STIP1) and NCAM1 (also known as CD56) were especially promising PrP C binding partners [39,40]. As a co-chaperone protein, STI1 coordinates the functions of heat-shock protein 70 (HSP70) and 90 (HSP90) in protein folding [41], whereas NCAM1 is a cell adhesion protein and member of the immunoglobulin superfamily directing cellcell and cell-matrix interactions [42].…”

Section: Intracellular Localisation Of Prp C In the Human Pancreasmentioning

confidence: 61%

“…Separately, co-registration of PrP C at the membrane with NCAM1 may support a putative function in cell signalling, differentiation and morphogenesis in the human pancreas [39,40,45]. For example, Santuccione et al [57] have shown that PrP C mediates the recruitment of NCAM1 to lipid rafts leading to cellular signalling through activation of the proto-oncogene, tyrosine kinase, FYN.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Altered cellular localisation and expression, together with unconventional protein trafficking, of prion protein, PrPC, in type 1 diabetes

et al. 2021

View full text Add to dashboard Cite

Aims/hypothesis Normal cellular prion protein (PrP C ) is a conserved mammalian glycoprotein found on the outer plasma membrane leaflet through a glycophosphatidylinositol anchor. Although PrP C is expressed by a wide range of tissues throughout the body, the complete repertoire of its functions has not been fully determined. The misfolded pathogenic isoform PrP Sc (the scrapie form of PrP) is a causative agent of neurodegenerative prion diseases. The aim of this study is to evaluate PrP C localisation, expression and trafficking in pancreases from organ donors with and without type 1 diabetes and to infer PrP C function through studies on interacting protein partners. Methods In order to evaluate localisation and trafficking of PrP C in the human pancreas, 12 non-diabetic, 12 type 1 diabetic and 12 autoantibody-positive organ donor tissue samples were analysed using immunofluorescence analysis. Furthermore, total RNA was isolated from 29 non-diabetic, 29 type 1 diabetic and 24 autoantibody-positive donors to estimate PrP C expression in the human pancreas. Additionally, we performed PrP C -specific immunoblot analysis on total pancreatic protein from non-diabetic and type 1 diabetic organ donors to test whether changes in PrP C mRNA levels leads to a concomitant increase in PrP C protein levels in human pancreases. Results In non-diabetic and type 1 diabetic pancreases (the latter displaying both insulin-positive [INS(+)] and -negative [INS(−)] islets), we found PrP C in islets co-registering with beta cells in all INS(+) islets and, strikingly, unexpected activation of PrP C in alpha cells within diabetic INS(−) islets. We found PrP C localised to the plasma membrane and endoplasmic reticulum (ER) but not the Golgi, defining two cellular pools and an unconventional protein trafficking mechanism bypassing the Golgi. We demonstrate PrP C co-registration with established protein partners, neural cell adhesion molecule 1 (NCAM1) and stressinducible phosphoprotein 1 (STI1; encoded by STIP1) on the plasma membrane and ER, respectively, linking PrP C function with cyto-protection, signalling, differentiation and morphogenesis. We demonstrate that both PRNP (encoding PrP C ) and STIP1 gene expression are dramatically altered in type 1 diabetic and autoantibody-positive pancreases. Conclusions/interpretation As the first study to address PrP C expression in non-diabetic and type 1 diabetic human pancreas, we provide new insights for PrP C in the pathogenesis of type 1 diabetes. We evaluated the cell-type specific expression of PrP C in the human pancreas and discovered possible connections with potential interacting proteins that we speculate might address mechanisms relevant to the role of PrP C in the human pancreas.

show abstract

Section: Intracellular Localisation Of Prp C In the Human Pancreasmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Altered cellular localisation and expression, together with unconventional protein trafficking, of prion protein, PrPC, in type 1 diabetes

et al. 2021

View full text Add to dashboard Cite

show abstract

“…One possibility is the cochaperone protein, heat shock protein stress induced phosphoprotein 1 (STI1, Fig. 2) (see da Fonseca et al, 2021;Lackie et al, 2017;Linden, 2017). STI1 coordinates 70 kDa heat shock proteins (HSP70) and 90 kDa heat shock proteins (HSP90) in the process of protein folding, both of which have been linked to neurodegenerative diseases (see Lackie et al, 2017).…”

Section: Molecular Control Of Oaβ42-dependent Modulation Of Memorymentioning

confidence: 99%

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

Murphy¹

2021

Preprint

View full text Add to dashboard Cite

Alzheimer’s Disease is defined as progressive memory loss coincident with accumulation of aggregated amyloid beta and phosphorylated tau. Identifying the relationship between these features has guided Alzheimer’s Disease research for decades, principally with the view that aggregated proteins drive a neurodegenerative process. Here I propose that amyloid beta and phospho-tau write-protect and tag neuroplastic changes as they form, protecting and insuring established neuroplasticity from corruption. In way of illustration, binding of oligomeric amyloid beta to the prion receptor is presented as an example possible mechanism. The write-protecting process is conjected to occur at least partially under the governance of isodendritic neuromodulators such as norepinephrine and acetylcholine. Coincident with aging, animals are exposed to accumulating amounts of memorable information. Compounded with recent increases in life expectancy and exposure to information-rich environments this causes aggregating proteins to reach unforeseen toxic levels as mnemonic circuits overload. As the brain cannot purposefully delete memories nor protect against overaccumulation of aggregating proteins, the result is catastrophic breakdown on cellular and network levels causing memory loss.

show abstract

“…33,34 Sti1 also interacts with many different aggregation prone proteins, [35][36][37] including the mammalian prion protein. [38][39][40] Although Hsp90 has been shown to interact with TDP-43, it remains unclear whether Hsp90 and its co-chaperones modulate TDP-43 toxicity. Here we report that Hsp90 and its co-chaperones, particularly Sti1, regulate TDP-43 aggregation and toxicity in yeast and mammalian cell models.…”

Section: Introductionmentioning

confidence: 99%

Hsp90 and its co‐chaperone Sti1 control TDP‐43 misfolding and toxicity

et al. 2021

View full text Add to dashboard Cite

Protein misfolding is a central feature of most neurodegenerative diseases. Molecular chaperones can modulate the toxicity associated with protein misfolding, but it remains elusive which molecular chaperones and co-chaperones interact with specific misfolded proteins. TDP-43 misfolding and inclusion formation are a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Using yeast and mammalian neuronal cells we find that Hsp90 and its co-chaperone Sti1 have the capacity to alter TDP-43 misfolding, inclusion formation, aggregation, and cellular toxicity. Our data also demonstrate that impaired Hsp90 function sensitizes cells to TDP-43 toxicity and that Sti1 specifically interacts with and strongly modulates TDP-43 toxicity in a dose-dependent manner. Our study thus uncovers a previously unrecognized tie between Hsp90, Sti1, TDP-43 misfolding, and cellular toxicity.

show abstract

The multiple functions of the co-chaperone stress inducible protein 1

Cited by 15 publications

References 105 publications

Altered cellular localisation and expression, together with unconventional protein trafficking, of prion protein, PrPC, in type 1 diabetes

Altered cellular localisation and expression, together with unconventional protein trafficking, of prion protein, PrPC, in type 1 diabetes

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

Hsp90 and its co‐chaperone Sti1 control TDP‐43 misfolding and toxicity

Contact Info

Product

Resources

About