Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing

The multidomain scaffold protein p62 (also called sequestosome-1) is involved in autophagy, antimicrobial immunity, and oncogenesis. Mutations in SQSTM1, which encodes p62, are linked to hereditary inflammatory conditions such as Paget’s disease of the bone, frontotemporal dementia (FTD), amyotrophic lateral sclerosis, and distal myopathy with rimmed vacuoles. Here, we report that p62 was proteolytically trimmed by the protease caspase-8 into a stable protein, which we called p62TRM. We found that p62TRM, but not full-length p62, was involved in nutrient sensing and homeostasis through the mechanistic target of rapamycin complex 1 (mTORC1). The kinase RIPK1 and caspase-8 controlled p62TRM production and thus promoted mTORC1 signaling. An FTD-linked p62 D329G polymorphism and a rare D329H variant could not be proteolyzed by caspase-8, and these noncleavable variants failed to activate mTORC1, thereby revealing the detrimental effect of these mutations. These findings on the role of p62TRM provide new insights into SQSTM1-linked diseases and mTORC1 signaling.
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Articles Source Type: news

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Abstract The multidomain scaffold protein p62 (also called sequestosome-1) is involved in autophagy, antimicrobial immunity, and oncogenesis. Mutations in SQSTM1, which encodes p62, are linked to hereditary inflammatory conditions such as Paget's disease of the bone, frontotemporal dementia (FTD), amyotrophic lateral sclerosis, and distal myopathy with rimmed vacuoles. Here, we report that p62 was proteolytically trimmed by the protease caspase-8 into a stable protein, which we called p62TRM We found that p62TRM, but not full-length p62, was involved in nutrient sensing and homeostasis through the mechanistic targ...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research
s MH, Vorgerd M, Eichinger L, Schröder R Abstract Heterozygous missense mutations in the human VCP gene cause inclusion body myopathy associated with Paget disease of bone and fronto-temporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS). The exact molecular mechanisms by which VCP mutations cause disease manifestation in different tissues are incompletely understood. In the present study, we report the comprehensive analysis of a newly generated R155C VCP knock-in mouse model, which expresses the ortholog of the second most frequently occurring human pathogenic VCP mutation. Heterozygous R155C VC...
Source: Biochemical and Biophysical Research communications - Category: Biochemistry Authors: Tags: Biochem Biophys Res Commun Source Type: research
t S Abstract VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). We analyzed here the in vivo role of Vcp and its novel interactor Washc4/Swip (WASH complex subunit 4) in the vertebrate model zebrafish (Danio rerio). We...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research
Le Ber I Abstract Valosin-containing protein (VCP) mutations are rare causes of autosomal dominant frontotemporal dementias associated with Paget's disease of bone, inclusion body myopathy, and amyotrophic lateral sclerosis. We analyzed the VCP gene in a cohort of 199 patients with frontotemporal dementia and identified 7 heterozygous mutations in unrelated families, including 3 novel mutations segregating with dementia. This expands the VCP mutation spectrum and suggests that although VCP mutations are rare (3.5% in this study), the gene should be analyzed even in absence of the full syndromic complex. Reporting...
Source: Neurobiology of Aging - Category: Geriatrics Authors: Tags: Neurobiol Aging Source Type: research
Inclusion Body Myopathy (IBM) associated with Paget's disease of the bone (PDB) and/or frontotemporal dementia (FTD) or Multisystem Proteinopathy (OMIM 167320) or more commonly called IBMPFD or VCP disease, was first reported by Kimonis et al. (2000) [1]. VCP disease comprises other less common phenotypes including amyotrophic lateral sclerosis (ALS), Parkinson's disease, cardiomyopathy, sensory motor axonal neuropathy, and sphincter disturbance [2 –6]. IBMPFD is an underdiagnosed disease that has been reported in greater than 100 families worldwide, but is more commonly found in the United States and Europe.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Valosin-containing protein (VCP) is a ubiquitous protein, being broadly expressed in several human body systems [1]. More than 45 missense mutations in the VCP gene have been associated with several disease conditions, collectively known as ‘multisystem proteinopathies’: these include early-onset Paget disease of the bone (PDB), myopathy with rimmed vacuoles or inclusion body myopathy (IBM), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) [2, 3].. Myopathy is the most common clinical feature of these conditio ns, mainly affecting proximal muscles.
Source: Journal of the Neurological Sciences - Category: Neurology Authors: Tags: Letter to the Editor Source Type: research
CONCLUSIONS: hnRNPA3 pathology was identified in motor neurons of ALS patients with C9orf72 repeat expansions, implicating hnRNPA3 in the pathogenesis of C9orf72-linked ALS. hnRNPA3 warrants further investigation into the pathogenesis of ALS linked to C9orf72. This study also determined that HNRNP mutations are not a common cause of FALS and SALS in Australia. PMID: 29131108 [PubMed - as supplied by publisher]
Source: Neuro-Degenerative Diseases - Category: Neurology Authors: Tags: Neurodegener Dis Source Type: research
Conclusions: hnRNPA3 pathology was identified in motor neurons of ALS patients with C9orf72 repeat expansions, implicating hnRNPA3 in the pathogenesis ofC9orf72-linked ALS. hnRNPA3 warrants further investigation into the pathogenesis of ALS linked toC9orf72. This study also determined thatHNRNP mutations are not a common cause of FALS and SALS in Australia.Neurodegener Dis 2017;17:304-312
Source: Neurodegenerative Diseases - Category: Neurology Source Type: research
Publication date: Available online 21 September 2017 Source:Journal of Genetics and Genomics Author(s): Dwayne J. Byrne, Mark J. Harmon, Jeremy C. Simpson, Craig Blackstone, Niamh C. O'Sullivan The VCP-Ufd1-Npl4 complex regulates proteasomal processing within cells by delivering ubiquitinated proteins to the proteasome for degradation. Mutations in VCP are associated with two neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD), and extensive study has revealed crucial functions of VCP within neurons. By contrast, ...
Source: Journal of Genetics and Genomics - Category: Genetics & Stem Cells Source Type: research
The valosin-containing protein (VCP) is involved in a plethora of cellular processes including membrane dynamics, DNA damage response, and protein quality control.1 Its essential role in humans is highlighted by diverse clinical phenotypes linked to VCP mutations: (1) inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD); (2) amyotrophic lateral sclerosis; (3) Charcot-Marie-Tooth disease type 2; and (4) hereditary spastic paraplegia (reviewed by Evangelista et al.2). Moreover, mutant VCP has been implicated in the pathogenesis of Parkinson disease (PD).3
Source: Neurology - Category: Neurology Authors: Tags: All Medical/Systemic disease, Parkinson's disease/Parkinsonism, Peripheral neuropathy, Muscle disease CLINICAL/SCIENTIFIC NOTES Source Type: research
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