Abstract
Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system, and defective clearance of these protein aggregates results in proteotoxicity and cell death. Recently, we found that the eIF2α kinase heme-regulated inhibitory (HRI) induced a cytosolic unfolded protein response to prevent aggregation of innate immune signalosomes, but whether HRI acts as a general sensor of proteotoxicity in the cytosol remains unclear. Here we show that HRI controls autophagy to clear cytosolic protein aggregates when the ubiquitin-proteasome system is inhibited. We further report that silencing the expression of HRI resulted in decreased levels of BAG3 and HSPB8, two proteins involved in chaperone-assisted selective autophagy, suggesting that HRI may control proteostasis in the cytosol at least in part through chaperone-assisted selective autophagy. Moreover, knocking down the expression of HRI resulted in cytotoxic accumulation of overexpressed α-synuclein, a protein known to aggregate in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In agreement with these data, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month-old Hri−/− mice as compared with Hri+/+ littermates. Moreover, aged Hri−/− mice showed accumulation of misfolded α-synuclein in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to α-synucleinopathies in humans. Together, these results suggest that HRI contributes to a general cytosolic unfolded protein response that could be leveraged to bolster the clearance of cytotoxic protein aggregates.
Highlights
Synuclein (Parkinson’s disease and other synucleinopathies), tau (Alzheimer’s disease and tauopathies), and TDP-43 [1]
This regulatory pathway, dependent on Heme-regulated kinase inhibitor (HRI), the heat shock protein heat shock protein 8 (HSPB8), eIF2α, activating transcription factor 4 (ATF4) and ATF3, was coined the cytosolic unfolded protein response, as it shares similarities with the pathway of regulation of protein folding in endoplasmic reticulum known as the unfolded protein response
It is not surprising that the stresses detected by the integrated stress response (ISR) relate to protein homeostasis, such as amino acid starvation or endoplasmic reticulum stress caused by protein misfolding in this organelle
Summary
Synuclein (Parkinson’s disease and other synucleinopathies), tau (Alzheimer’s disease and tauopathies), and TDP-43 (amyotrophic lateral sclerosis and frontotemporal dementia) [1]. Proteasome inhibition, but not inhibition of autophagy using bafilomycin treatment, resulted in the accumulation of ubiquitinated proteins in HRI-silenced HEK293T cells, as observed by Western blotting on whole cellular extracts (Fig. 1D and Fig. S1B), suggesting that HRI silencing is in epistasis with autophagy rather than the UPS pathways.
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