Human High Temperature Requirement Serine Protease A1 (HTRA1) Degrades Tau Protein Aggregates

Tennstaedt, Annette; Pöpsel, Simon; Truebestein, Linda; Hauske, Patrick; Brockmann, Anke; Schmidt, Nina; Irle, Inga; Saccá, Barbara; Niemeyer, Christof M.; Brandt, Roland; Księżak-Reding, Hanna; Tirniceriu, Anca; Egensperger, Rupert; Baldi, Alfonso; Dehmelt, Leif; Kaiser, Markus; Huber, Robert; Clausen, Tim; Ehrmann, Michael

doi:10.1074/jbc.m111.316232

Cited by 82 publications

(89 citation statements)

References 62 publications

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“…Furthermore, HtrA1 colocalizes with amyloid deposits in human brain samples [36]. HtrA1 also degrades aggregated and fibrillar tau protein; neuronal cells and patient brains accumulate less tau, neurofibrillary tangles, and neuritic plaques, respectively, when HtrA1 is expressed at elevated levels [43,44]. These data suggest that HtrA1 performs regulated proteolysis during protein quality control which protects the brain against accumulation of amyloid deposits and tau neurofibrillary tangles e the hallmarks of the Alzheimer's disorder.…”

Section: Human Htra Proteins In Cellular Physiology and Pathogenesismentioning

confidence: 85%

Structural insights into the activation mechanisms of human HtrA serine proteases

Żurawa-Janicka

Wenta

Jarzab

et al. 2017

Archives of Biochemistry and Biophysics

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Section: Human Htra Proteins In Cellular Physiology and Pathogenesismentioning

confidence: 85%

Structural insights into the activation mechanisms of human HtrA serine proteases

Żurawa-Janicka

Wenta

Jarzab

et al. 2017

Archives of Biochemistry and Biophysics

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“…This function of IGF-1 supports the concept that HtrA1 function may protect from an age-related disease (45,76) such as NvAMD. In addition to NvAMD, HtrA1 has been implicated in other age-related disorders like arthritis (36,46) and Alzheimer's disease (45,77). HtrA1 expression increases with age (78).…”

Section: Discussionmentioning

confidence: 99%

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Jacobo

DeAngelis

Kim

et al. 2013

Molecular and Cellular Biology

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Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular agerelated macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD. Single nucleotide polymorphisms (SNPs) that fall within the coding region have the potential to alter the amino acid sequence of a gene's product and therefore can serve as a Rosetta stone for understanding the pathogenesis of human disorders (1, 2). A curiosity that emerged from human genome-wide association studies is that exonic SNPs that do not alter the amino acid sequence of the protein product (i.e., SNPs that are synonymous) are as common as SNPs that do (i.e., SNPs that are nonsynonymous) (3). Furthermore, some of the disease-associated synonymous SNPs constitute the molecular underpinnings of pathology, meaning that they are enriched in affected human subjects and alter the gene product. For the majority (95%) of disease-associated synonymous SNPs, aberrant gene products were attributed to unstable mRNA transcripts with a reduced half-life or mutations in splice sites that resulted in exon skipping (4, 5). In other cases, synonymous SNPs caused translational defects independently of mRNA splicing errors (6-9).A parsimonious mechanism by which synonymous SNPs impact the integrity of protein products involves the alteration of codon usage. In vivo, folding of nascent proteins proceeds cotranslationally (10, 11) and is influenced by the rate of ribosome transit through the mRNA template. What distinguishes synonymous codons that encode a given degenerate amino acid is the abundance of their corresponding tRNA, which is lower for infrequently used codons than for frequently used codons (12, 13). Consequently, codon frequency can influence the rate of translation. Of note, codon bias has been widely described in prokaryotes and single-celled eukaryotes but less extensively in complex eukaryotes.In humans, correlations between optimum codon usage and either protein expression...

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Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that HtrA1 cleaves tau and the amyloid precursor protein (APP) (76)(77)(78), which is predicted to promote protection in the AD context. Furthermore, HtrA1 levels and activity are increased in response to the development of AD pathology (77). It was also recently established that HtrA1 degrades apoE4 more rapidly than apoE3 (22), which may contribute to the overall reduced levels of apoE4 detected in AD brain tissues as compared to apoE3.…”

Section: Discussionmentioning

confidence: 99%

The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis

Muñoz

Liu

Ruberu

et al. 2018

Journal of Biological Chemistry

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Apolipoprotein-E (apoE) is a glycoprotein highly expressed in the brain, where it appears to play a role in lipid transport, b-amyloid clearance, and neuronal signaling. ApoE proteolytic fragments are also present in the brain, but the enzymes responsible for apoE fragmentation are unknown, and the biological activity of specific apoE fragments remains to be determined. Here we utilised SK-N-SH neuroblastoma cells differentiated into neurons with all-trans retinoic acid (ATRA) to study extracellular apoE proteolysis. ApoE fragments were detectable in culture supernatants after 3 days, and their levels were increased for up to 9 days in the presence of ATRA. The concentration of apoE fragments was positively correlated with levels of the neuronal maturation markers (PSD95 and SMI32). The most abundant apoE fragments were 25 kDa and 28 kDa N-terminal fragments that both contained sialylated glycosylation and bound to heparin. We detected apoE fragments only in the extracellular milieu and not in cell lysates, suggesting that an extracellular protease contributes to apoE fragmentation.Of note, siRNA-mediated knockdown of high-temperature requirement serine peptidase A1 (HtrA1) and a specific HtrA1 inhibitor reduced apoE 25 kDa fragment formation by 41% and 86%, respectively. Recombinant 25-kDa fragment apoE and full-length apoE both stimulated neuritogenesis in vitro, increasing neuroblastoma neurite growth by more than 2-fold over a 6-day period. This study provides a cellular model for assessing apoE proteolysis, indicates that HtrA1 regulates apoE 25-kDa fragment formation under physiological conditions, and reveals a new neurotrophic function for the apoE 25-kDa fragment. ________________________________________

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Human High Temperature Requirement Serine Protease A1 (HTRA1) Degrades Tau Protein Aggregates

Cited by 82 publications

References 62 publications

Structural insights into the activation mechanisms of human HtrA serine proteases

Structural insights into the activation mechanisms of human HtrA serine proteases

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis

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