Recent from talks
SSHHPS
Knowledge base stats:
Talk channels stats:
Members stats:
SSHHPS
SSHHPS is an acronym for short stretches of homologous host pathogen sequences. The acronym was first coined by Legler in a 2019 publication. Legler used BLAST to search for host protein substrates for the nsP2 protease of the Venezuelan equine encephalitis virus (VEEV) and the protease from Zika virus. These viruses are Group 4 (+)ssRNA viruses. Short ~20–25 amino acid sequences from the viral polyprotein containing the scissile bond were used to search the human proteome. Many of the sequence alignments were spurious, while some matched well with the residues surrounding the scissile bond. When all known host proteins shown to be cut by viral proteases were consolidated into a table, it became clear that the targets were not random. Most were related to innate immunity while others appeared to be related to viral pathogenesis and the virus-induced phenotype. Some hits were related to both. The list of experimentally confirmed host targets of Group IV viral proteases included key proteins involved in innate immunity e.g. MAVS, RIG-I, STING, TRIF, and TRIM14. In 1984, one of the first host proteins shown to be cut by a viral protease was histone H3 by foot-and-mouth disease virus. The histone tails are strategic targets of the viral proteases, the cleavage can shut down host cell transcription and the many effects of interferon.
Viral proteases recognize sequence motifs. The subsite tolerances in the protease can vary, leading to the recognition of many sequences. The protease is a complement to many peptides.
Silencing can occur at the level of DNA, RNA, and protein. The 3rd mechanism of silencing would involve proteases and proteins. SSHHPS cleavage is a type of target specific co- or post-translational silencing.
Silencing can occur at the level of DNA, RNA, and Protein. SSHHPS are short stretches of homologous host pathogen sequences. These sequences can be found at the viral protease cleavage sites, they correspond to specific proteins in the host. The cleavage of these sequences can be co- or post-translational. Original figure can be found in Morazzani, et al.
Using PHI-BLAST and a sequence pattern (e.g. L[RK]GG) a shorter list of host targets could be obtained; however, the searches still produced hundreds of host targets (YouTube Video). To sort them and rank order them Legler used clustering. Plotting 'percent positives' vs. 'alignment length' from the PHI-BLAST output file, the cleavable proteins were found to cluster and localize to the right of the graph. The hit lists could now be sorted by alignment length and percent positives and a rank-ordered list could be produced. At the top of the list are the most likely substrates and at the bottom the less likely substrates. This and experimental data became the basis for the first sequence-to-symptom software for viruses. An example of the software output can be found here.
After sorting the hits, Legler found that the hits at the top of the list had similarities to the virus-induced phenotype. For the COVID-19 SARS-CoV-2 papain-like protease (PLpro), cardiac myosins were the strongest predicted hit (MYH6, MYH7); MYOM1, POT1, VWF, PROS1, HER4, and FOXP3 were also predicted and the sequences were shown to be cleavable. A group at UCSF, showed the cleavage of myofibrils in cardiomyocytes after infection with SARS-CoV-2. Fragments of the sarcomere are still visible showing that the cleavage of the myofibrils occurs post-translationally and after the assembly of the myofibril. The viral proteases have also been suspected in COVID coagulopathy. The PLpro of SARS-CoV-2 was able to cut sequences in PROS1 and VWF.
Zika virus has been associated with microcephaly and anencephaly. Using the sorting and graphical method described above, hits related to these phenotypes emerged, such as GIT1, FOXG1, and SFRP1. GIT1 knockout mice develop microcephaly. Mice and rats have not been shown to develop microcephaly after infection with Zika virus (ZIKV). However, Goodfellow, et al. showed that chickens can produce microcephaly when infected with ZIKV. Both humans and chickens have the same sequence at the predicted cleavage site in SFRP1. SFRP1 is a predicted host protein substrate for the Zika viral protease. The sequence is identical in humans and chickens, two species which both produce microcephaly after infection with Zika virus. SFRP1 is part of the Wnt signaling pathway. The loss of function of more than one protein may be needed to produce the virus-induced phenotype.
The SSHHPS for Pipistrellus bat coronavirus HKU5 (Bat-CoV HKU5) have been predicted and can be found here. Analysis of the PLpro SSHHPS in HKU5 identified hits related to neurodevelopmental disorders, epilepsy, seizures, respiratory effects, lung inflammation, spinocerebellar ataxia, microphthalmia, ocular abnormalities, IBS, anhidrosis, hydrocephalus, hearing loss, elevated hemoglobin and hematocrit, skeletal dysplasia, microcephaly, nephrotic syndrome, among others. ADGRA2 was among the predictions.
Hub AI
SSHHPS AI simulator
(@SSHHPS_simulator)
SSHHPS
SSHHPS is an acronym for short stretches of homologous host pathogen sequences. The acronym was first coined by Legler in a 2019 publication. Legler used BLAST to search for host protein substrates for the nsP2 protease of the Venezuelan equine encephalitis virus (VEEV) and the protease from Zika virus. These viruses are Group 4 (+)ssRNA viruses. Short ~20–25 amino acid sequences from the viral polyprotein containing the scissile bond were used to search the human proteome. Many of the sequence alignments were spurious, while some matched well with the residues surrounding the scissile bond. When all known host proteins shown to be cut by viral proteases were consolidated into a table, it became clear that the targets were not random. Most were related to innate immunity while others appeared to be related to viral pathogenesis and the virus-induced phenotype. Some hits were related to both. The list of experimentally confirmed host targets of Group IV viral proteases included key proteins involved in innate immunity e.g. MAVS, RIG-I, STING, TRIF, and TRIM14. In 1984, one of the first host proteins shown to be cut by a viral protease was histone H3 by foot-and-mouth disease virus. The histone tails are strategic targets of the viral proteases, the cleavage can shut down host cell transcription and the many effects of interferon.
Viral proteases recognize sequence motifs. The subsite tolerances in the protease can vary, leading to the recognition of many sequences. The protease is a complement to many peptides.
Silencing can occur at the level of DNA, RNA, and protein. The 3rd mechanism of silencing would involve proteases and proteins. SSHHPS cleavage is a type of target specific co- or post-translational silencing.
Silencing can occur at the level of DNA, RNA, and Protein. SSHHPS are short stretches of homologous host pathogen sequences. These sequences can be found at the viral protease cleavage sites, they correspond to specific proteins in the host. The cleavage of these sequences can be co- or post-translational. Original figure can be found in Morazzani, et al.
Using PHI-BLAST and a sequence pattern (e.g. L[RK]GG) a shorter list of host targets could be obtained; however, the searches still produced hundreds of host targets (YouTube Video). To sort them and rank order them Legler used clustering. Plotting 'percent positives' vs. 'alignment length' from the PHI-BLAST output file, the cleavable proteins were found to cluster and localize to the right of the graph. The hit lists could now be sorted by alignment length and percent positives and a rank-ordered list could be produced. At the top of the list are the most likely substrates and at the bottom the less likely substrates. This and experimental data became the basis for the first sequence-to-symptom software for viruses. An example of the software output can be found here.
After sorting the hits, Legler found that the hits at the top of the list had similarities to the virus-induced phenotype. For the COVID-19 SARS-CoV-2 papain-like protease (PLpro), cardiac myosins were the strongest predicted hit (MYH6, MYH7); MYOM1, POT1, VWF, PROS1, HER4, and FOXP3 were also predicted and the sequences were shown to be cleavable. A group at UCSF, showed the cleavage of myofibrils in cardiomyocytes after infection with SARS-CoV-2. Fragments of the sarcomere are still visible showing that the cleavage of the myofibrils occurs post-translationally and after the assembly of the myofibril. The viral proteases have also been suspected in COVID coagulopathy. The PLpro of SARS-CoV-2 was able to cut sequences in PROS1 and VWF.
Zika virus has been associated with microcephaly and anencephaly. Using the sorting and graphical method described above, hits related to these phenotypes emerged, such as GIT1, FOXG1, and SFRP1. GIT1 knockout mice develop microcephaly. Mice and rats have not been shown to develop microcephaly after infection with Zika virus (ZIKV). However, Goodfellow, et al. showed that chickens can produce microcephaly when infected with ZIKV. Both humans and chickens have the same sequence at the predicted cleavage site in SFRP1. SFRP1 is a predicted host protein substrate for the Zika viral protease. The sequence is identical in humans and chickens, two species which both produce microcephaly after infection with Zika virus. SFRP1 is part of the Wnt signaling pathway. The loss of function of more than one protein may be needed to produce the virus-induced phenotype.
The SSHHPS for Pipistrellus bat coronavirus HKU5 (Bat-CoV HKU5) have been predicted and can be found here. Analysis of the PLpro SSHHPS in HKU5 identified hits related to neurodevelopmental disorders, epilepsy, seizures, respiratory effects, lung inflammation, spinocerebellar ataxia, microphthalmia, ocular abnormalities, IBS, anhidrosis, hydrocephalus, hearing loss, elevated hemoglobin and hematocrit, skeletal dysplasia, microcephaly, nephrotic syndrome, among others. ADGRA2 was among the predictions.
Recent media