Sequestosome-1 is a protein that in humans is encoded by the SQSTM1 gene. [5] [6] [7] Also known as the ubiquitin-binding protein p62, [8] it is an autophagosome cargo protein that targets other proteins that bind to it for selective autophagy. By interacting with GATA4 and targeting it for degradation, it can inhibit GATA-4 associated senescence and senescence-associated secretory phenotype. [9]
| Characteristic | Phenotype |
|---|---|
| Homozygote viability | Normal |
| Fertility | Normal |
| Body weight | Normal |
| Anxiety | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Hot plate | Normal |
| Dysmorphology | Normal |
| Indirect calorimetry | Normal |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Normal |
| Radiography | Normal |
| Body temperature | Normal |
| Eye morphology | Normal |
| Clinical chemistry | Normal |
| Haematology | Abnormal [10] |
| Peripheral blood lymphocytes | Normal |
| Micronucleus test | Normal |
| Heart weight | Normal |
| Salmonella infection | Normal [11] |
| Citrobacter infection | Normal [12] |
| All tests and analysis from [13] [14] |
Model organisms have been used in the study of SQSTM1 function. A conditional knockout mouse line, called Sqstm1tm1a(KOMP)Wtsi [15] [16] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. [17] [18] [19]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. [13] [20] Twenty two tests were carried out on homozygous mutant mice and one significant abnormality was observed: females had abnormal complete blood count parameters, including an increased red blood cell distribution width and increased mean platelet volume. [13]
Sequestosome 1 has been shown to interact with:
Receptor activator of nuclear factor κ B (RANK), also known as TRANCE receptor or TNFRSF11A, is a member of the tumor necrosis factor receptor (TNFR) molecular sub-family. RANK is the receptor for RANK-Ligand (RANKL) and part of the RANK/RANKL/OPG signaling pathway that regulates osteoclast differentiation and activation. It is associated with bone remodeling and repair, immune cell function, lymph node development, thermal regulation, and mammary gland development. Osteoprotegerin (OPG) is a decoy receptor for RANKL, and regulates the stimulation of the RANK signaling pathway by competing for RANKL. The cytoplasmic domain of RANK binds TRAFs 1, 2, 3, 5, and 6 which transmit signals to downstream targets such as NF-κB and JNK.
Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the NTRK1 gene.
Protein kinase C, zeta (PKCζ), also known as PRKCZ, is a protein in humans that is encoded by the PRKCZ gene. The PRKCZ gene encodes at least two alternative transcripts, the full-length PKCζ and an N-terminal truncated form PKMζ. PKMζ is thought to be responsible for maintaining long-term memories in the brain. The importance of PKCζ in the creation and maintenance of long-term potentiation was first described by Todd Sacktor and his colleagues at the SUNY Downstate Medical Center in 1993.
TRAF6 is a TRAF human protein.
TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene.
Tumor necrosis factor receptor type 1-associated DEATH domain protein is a protein that in humans is encoded by the TRADD gene.
IκBα is one member of a family of cellular proteins that function to inhibit the NF-κB transcription factor. IκBα inhibits NF-κB by masking the nuclear localization signals (NLS) of NF-κB proteins and keeping them sequestered in an inactive state in the cytoplasm. In addition, IκBα blocks the ability of NF-κB transcription factors to bind to DNA, which is required for NF-κB's proper functioning.
Mitogen-activated protein kinase 8 is a ubiquitous enzyme that in humans is encoded by the MAPK8 gene.
Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the MAP3K7 gene.
Protein kinase C iota type is an enzyme that in humans is encoded by the PRKCI gene.
B-cell lymphoma/leukemia 10 is a protein that in humans is encoded by the BCL10 gene. Like BCL2, BCL3, BCL5, BCL6, BCL7A, and BCL9, it has clinical significance in lymphoma.
Tumor necrosis factor, alpha-induced protein 3 or A20 is a protein that in humans is encoded by the TNFAIP3 gene.
Receptor-interacting serine/threonine-protein kinase 2 is an enzyme that in humans is encoded by the RIPK2 gene.
Mitogen-activated protein kinase kinase kinase 14 also known as NF-kappa-B-inducing kinase (NIK) is an enzyme that in humans is encoded by the MAP3K14 gene.
Mitogen-activated protein kinase kinase kinase 7-interacting protein 2 is an enzyme that in humans is encoded by the MAP3K7IP2 gene.
Mitogen-activated protein kinase kinase kinase 7-interacting protein 1 is an enzyme that in humans is encoded by the TAB1 gene.
Dual specificity mitogen-activated protein kinase kinase 5 is an enzyme that in humans is encoded by the MAP2K5 gene.
Serine/threonine-protein kinase SMG1 is an enzyme that in humans is encoded by the SMG1 gene. SMG1 belongs to the phosphatidylinositol 3-kinase-related kinase protein family.
Microtubule-associated serine/threonine-protein kinase 2 is an enzyme that in humans is encoded by the MAST2 gene. The protein encoded by this gene controls TRAF6 and NF-kappaB activity.
BIM-1 and the related compounds BIM-2, BIM-3, and BIM-8 are bisindolylmaleimide-based protein kinase C (PKC) inhibitors. These inhibitors also inhibit PDK1 explaining the higher inhibitory potential of LY33331 compared to the other BIM compounds a bisindolylmaleimide inhibitor toward PDK1.
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