Chaperone AMPylation modulates aggregation and toxicity of neurodegenerative disease-associated polypeptides

Abstract

SignificanceProtein AMPylation in eukaryotes is a comparatively understudied posttranslational modification. With the exception of yeast, all eukaryotes have the enzymatic machinery required to execute this modification. Members of the heat shock protein family in different cellular compartments appear to be preferred targets for AMPylation, but it has proven challenging to adduce its biological function. We show that genetic modifications that affect AMPylation status, through generation of null alleles and a constitutively active version of the AMPylase FIC-1, can have a major impact on the susceptibility of Caenorhabditis elegans to neurodegenerative conditions linked to protein aggregation.

CryoAPEX - an electron tomography tool for subcellular localization of membrane proteins

“…The first Fic proteins, VopS and IbpA, were described in the pathogenic bacteria Vibrio parahemolyticus and Histophilus somni , respectively, where they serve as secreted bacterial effectors that induce toxicity in host cells by adenylylating/AMPylating and inactivating small GTPases (Mattoo et al, 2011; Worby et al, 2009; Xiao et al, 2010; Yarbrough et al, 2009; Zekarias et al, 2010) . Fic proteins have also been implicated in bacterial cell division and persister cell formation, protein translation, cellular trafficking, and neurodegeneration (Garcia-Pino et al, 2014; Harms et al, 2015; Mukherjee et al, 2011; Truttmann et al, 2018) .…”

The YdiU Domain Modulates Bacterial Stress Signaling through Mn2+-dependent UMPylation

“…In higher eukaryotes, the activities of endoplasmic reticulum (ER)-localized Hsp70 chaperone BiP and cytosolic chaperone Ssa2 are regulated by AMPylation mediated by Fic domain proteins in response to unfolded protein stress or heat stress 40,41,42 . Recently, aggregation and toxicity of neurodegenerative disease-associated polypeptides was found to be modulated by the AMPylation of chaperone in elegan 43 .…”

Alpha-Synuclein is a Target of Fic-mediated Adenylylation/AMPylation: Implications for Parkinson’s Disease

“…Further, our discovery of BiP as the elusive target for the human Fic protein, HYPE, has unveiled Fic-mediated adenylylation as a critical step in UPR regulation and the cell's ability to cope with misfolded proteins [7]. Further, through its ability to manipulate 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 chaperone activity, Fic-mediated adenylylation has recently been linked to neurodegeneration [29].…”

“…How HYPE interacts physiologically with these non-ER localized proteins is unclear [54], though a recent report reveals that a mass exodus of ER resident proteins occurs in response to ER Ca 2+ depletion [41]. Additionally in C. elegans, HYPE is reported to be partially present in the cytosol in addition to the ER lumen [29].…”

“…Given this critical role for HYPE in how cells cope with stress from misfolded proteins and the direct correlation between αSyn accumulation, ER stress and PD progression, we reasoned that HYPE may play a role in PD, possibly via UPR regulation or direct interaction with αSyn. Indeed, a role for HYPE in neurodegeneration was recently reported in a C. elegans model, where activation of HYPE's adenylyltransferase activity was shown to induce neuroprotective aggregative effects of proteins like amyloid beta (Aβ), mutant Huntingtin (m-Htt), and αSyn through its manipulation of cytosolic Hsp70 chaperones [29]. We, too, have shown previously that HYPE can directly bind to misfolded proteins [7], and global proteomic analyses of adenylylated peptides by mass spectrometry indicate targets for HYPE other than BiP and related heat shock proteins [30,31].…”