TY  - JOUR
A1  - Alvarez-Castelao, Beatriz
A1  - TomDieck, Susanne
A1  - Fusco, Claudia Mariateresa
A1  - Donlin-Asp, Paul
A1  - Perez, Julio D
A1  - Schuman, Erin M.
T1  - The switch-like expression of heme-regulated kinase 1 mediates neuronal proteostasis following proteasome inhibition
T2  - eLife
N2  - We examined the feedback between the major protein degradation pathway, the ubiquitin-proteasome system (UPS), and protein synthesis in rat and mouse neurons. When protein degradation was inhibited, we observed a coordinate dramatic reduction in nascent protein synthesis in neuronal cell bodies and dendrites. The mechanism for translation inhibition involved the phosphorylation of eIF2α, surprisingly mediated by eIF2α kinase 1, or heme-regulated kinase inhibitor (HRI). Under basal conditions, neuronal expression of HRI is barely detectable. Following proteasome inhibition, HRI protein levels increase owing to stabilization of HRI and enhanced translation, likely via the increased availability of tRNAs for its rare codons. Once expressed, HRI is constitutively active in neurons because endogenous heme levels are so low; HRI activity results in eIF2α phosphorylation and the resulting inhibition of translation. These data demonstrate a novel role for neuronal HRI that senses and responds to compromised function of the proteasome to restore proteostasis.
KW  - proteostasis
KW  - protein synthesis
KW  - protein degradation
KW  - heme-regulated inhibitory kinase
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/85719
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-857198
SN  - 2050-084X
VL  - 9
IS  - e52714
PB  - eLife Sciences Publications
CY  - Cambridge
ER  -