Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system (UPS), 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 (cUPR) 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 UPS is inhibited. We further report that silencing HRI expression resulted in decreased levels of BAG3 and HSPB8, two proteins involved in chaperone-assisted selective autophagy (CASA), suggesting that HRI controls proteostasis in the cytosol at least in part through CASA. Moreover, knocking down the expression of HRI resulted in cytotoxic accumulation of over-expressed 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 to Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded α-synuclein, indicative of misfolded proteins, 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 cUPR that could be leveraged to bolster the clearance of cytotoxic protein aggregates.
Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system (UPS), and defective clearance of these protein aggregates results in proteotoxicity and cell death. Here we show that the eIF2α kinase HRI potentiates the autophagic clearance of cytosolic protein aggregates when the UPS is inhibited. In cells silenced for HRI, proteasome inhibition resulted in accumulation of aggresomes and ubiquitinated proteins, as well as cytotoxicity. Moreover, silencing of HRI resulted in cytotoxic accumulation of over-expressed α-synuclein, a protein known to aggregate in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In agreement, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month old Hri-/- mice as compared to Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded α-synuclein, indicative of misfolded proteins, 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 where it may contribute to impaired micturition and/or constipation. Together, these results suggest that HRI contributes to a general cytosolic unfolded protein response (cUPR) that could be leveraged to bolster the clearance of cytotoxic protein aggregates.
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