The sequestosome 1/p62 protein has been implicated in the regulation of a multitude of cellular processes such as NF-κB signaling, NRF2-driven oxidative stress response, protein turnover through the ubiquitin-proteas...The sequestosome 1/p62 protein has been implicated in the regulation of a multitude of cellular processes such as NF-κB signaling, NRF2-driven oxidative stress response, protein turnover through the ubiquitin-proteasome pathway and the autophagosome/lysosome pathway, apoptosis and cellular metabolism. The domain structure of p62 also reflects this functional complexity since the protein appears to be a mosaic of protein interaction domains and motifs. Deregulation of the level and function of p62 and/or p62 mutations have been linked to a number of human diseases including Paget＇s disease of the bone, obesity, liver diseases, tumorigenesis and neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer＇s disease. In this article, we review the current understanding of the involvement of p62 in cellular processes under physiologic and pathological conditions.展开更多
Background Alcohol-associated liver disease(ALD)is a global health problem without an effective treatment.Mallory-Denk body(MDB)is a protein aggregate commonly found in alcohol-associated hepatitis(AH).MDB primarily c...Background Alcohol-associated liver disease(ALD)is a global health problem without an effective treatment.Mallory-Denk body(MDB)is a protein aggregate commonly found in alcohol-associated hepatitis(AH).MDB primarily contains ubiquitinated proteins,cytokeratin 8 and sequestosome 1(SQSTM1)/p62.Stress granule(SG)is a cytosolic,membrane-less aggregate composed of various RNA-binding proteins and untranslated mRNA.However,the role and mechanisms of MDB and SG induced by alcohol and their implications in the pathogenesis of ALD remain largely unknown.Methods SQSTM1/p62 whole body knockout and matched wild-type mice were subjected to the Gao-binge alcohol model or fed a 3,5-diethoxycarbonyl-1,4-dihydrocollidine(DDC)diet alongside Gao-binge alcohol model.ALD mouse liver tissues and human AH liver tissues underwent immunohistochemistry(IHC)staining and western blot analysis for SG and MDB markers.Results We found that the livers of patients with AH had higher levels of SQSTM1/p62(MDB marker)and Ras-GTPase-activating protein-binding protein 1(an SG marker)using IHC staining,and these increased protein levels were enriched in detergent-insoluble fractions compared with healthy individuals.We further discovered that Gao-binge alcohol feeding increased insoluble SG markers,such as phosphorylated eukaryotic initiation factor 2 in mouse livers.Mice fed a DDC diet with Gao-binge alcohol had greater hepatic MDB formation and liver injury than those fed either diet alone.Loss of SQSTM1/p62 led to reduced protein aggregation involved in SGs and MDBs but increased liver injury in DDC plus Gao-binge alcohol-fed mice,indicating that SQSTM1/p62 is required for MDB formation and protects against alcohol-induced liver injury.Conclusion Chronic plus binge alcohol exposure increases hepatic MDBs and moderate levels of SGs.p62/SQSTM1 is critical for the formation but is not essential for the clearance of MDBs,a process that may act as an adaptive protective mechanism against ALD.展开更多
Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson＇s disease （PD）, respectively, which manifested with the selective vulnerability of neuronal ceils...Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson＇s disease （PD）, respectively, which manifested with the selective vulnerability of neuronal ceils in substantia nigra （SN） and striatum （STR） regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis.展开更多
文摘The sequestosome 1/p62 protein has been implicated in the regulation of a multitude of cellular processes such as NF-κB signaling, NRF2-driven oxidative stress response, protein turnover through the ubiquitin-proteasome pathway and the autophagosome/lysosome pathway, apoptosis and cellular metabolism. The domain structure of p62 also reflects this functional complexity since the protein appears to be a mosaic of protein interaction domains and motifs. Deregulation of the level and function of p62 and/or p62 mutations have been linked to a number of human diseases including Paget＇s disease of the bone, obesity, liver diseases, tumorigenesis and neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer＇s disease. In this article, we review the current understanding of the involvement of p62 in cellular processes under physiologic and pathological conditions.
基金supported by the National Institute of Health(NIH)funds R37 AA020518,R21 AA030617 and R01AA031230(W-XD),and R24AA025017(ZS).
文摘Background Alcohol-associated liver disease(ALD)is a global health problem without an effective treatment.Mallory-Denk body(MDB)is a protein aggregate commonly found in alcohol-associated hepatitis(AH).MDB primarily contains ubiquitinated proteins,cytokeratin 8 and sequestosome 1(SQSTM1)/p62.Stress granule(SG)is a cytosolic,membrane-less aggregate composed of various RNA-binding proteins and untranslated mRNA.However,the role and mechanisms of MDB and SG induced by alcohol and their implications in the pathogenesis of ALD remain largely unknown.Methods SQSTM1/p62 whole body knockout and matched wild-type mice were subjected to the Gao-binge alcohol model or fed a 3,5-diethoxycarbonyl-1,4-dihydrocollidine(DDC)diet alongside Gao-binge alcohol model.ALD mouse liver tissues and human AH liver tissues underwent immunohistochemistry(IHC)staining and western blot analysis for SG and MDB markers.Results We found that the livers of patients with AH had higher levels of SQSTM1/p62(MDB marker)and Ras-GTPase-activating protein-binding protein 1(an SG marker)using IHC staining,and these increased protein levels were enriched in detergent-insoluble fractions compared with healthy individuals.We further discovered that Gao-binge alcohol feeding increased insoluble SG markers,such as phosphorylated eukaryotic initiation factor 2 in mouse livers.Mice fed a DDC diet with Gao-binge alcohol had greater hepatic MDB formation and liver injury than those fed either diet alone.Loss of SQSTM1/p62 led to reduced protein aggregation involved in SGs and MDBs but increased liver injury in DDC plus Gao-binge alcohol-fed mice,indicating that SQSTM1/p62 is required for MDB formation and protects against alcohol-induced liver injury.Conclusion Chronic plus binge alcohol exposure increases hepatic MDBs and moderate levels of SGs.p62/SQSTM1 is critical for the formation but is not essential for the clearance of MDBs,a process that may act as an adaptive protective mechanism against ALD.
基金We are grateful to Drs. Ted Dawson and Jian Feng for generously providing the plasmids. We are also grateful to Professor Mark Bartlam from Nankai University, Tianjin, China for a critical reading of the manuscript. The research was supported by the National Basic Research Program （973 Program） （No. 2011 CB910903） from MOST and project （Grant Nos. 81130045, 31471300, 31271529, 301520103904） from the National Natural Science Foundation of China.
文摘Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson＇s disease （PD）, respectively, which manifested with the selective vulnerability of neuronal ceils in substantia nigra （SN） and striatum （STR） regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis.
