Drug Target and Biomarker: SQSTM1 (G8878)

Target Name: SQSTM1

NCBI ID: G8878

Drug Target and Biomarker: SQSTM1

SQSTM1 is involved in the clearance of protein waste material through autophagy and proteasomal degradation.
Impaired autophagy can contribute to the formation of drusen and age-related macular degeneration (AMD).
SQSTM1 plays a role in selective autophagy processes such as pexophagy, aggrephagy, and inflammasomophagy.
Phospho-p62 can competitively interact with Keap1, leading to the translocation and activation of Nrf2.
Morphine can inhibit mitophagy by suppressing the recruitment of Parkin to damaged mitochondria and interrupting the recognition of autophagosomes.
Sirt1 up-regulation can lead to p62 accumulation and contribute to hepatocellular carcinogenesis.

These viewpoints provide a comprehensive understanding of the multiple roles of SQSTM1 in autophagy, protein clearance, and disease processes.
Based on the provided context information, the key viewpoints related to SQSTM1 (also known as p62) are as follows:

Autophagy Inhibition and EMT: Autophagy inhibition induces epithelial-to-mesenchymal transition (EMT) in lung alveolar epithelial cells through the up-regulation of Snail2, indicating that this effect is likely dependent on the cellular context. Autophagy plays a role in managing oxidative and proteotoxic stress, and impairment of p62 oxidation can result in less autophagy induction under such stress conditions.

Age-Related Alveolar Injuries: Repetitive local micro-injuries to aging alveolar epithelium can lead to persistent activation of alveolar epithelial cells, which secrete profibrogenic factors and drive local myofibroblast differentiation. This implies that the accumulation of local injuries in aging lungs may contribute to fibrotic processes.

NRF2 and Cellular Processes: NRF2 plays a role in controlling primary ciliogenesis and the Hedgehog signaling pathway through distinct mechanisms, including the up-regulation of PTCH1 and increased expression of p62/SQSTM1, respectively. The dysregulation of NRF2 and p62 may impact primary cilia formation and Hh signaling.

Role of p62 in Mitophagy: The multivalent interaction of p62 and the protein Nur77 triggers phase separation, which sequesters damaged mitochondria and directs cargo mitochondria to the autophagic machinery. This suggests that p62 plays a role in mitophagy, the selective degradation of mitochondria through autophagy.

p62 Signaling and Osteoblastogenesis: The p62-ZZ domain pathway, activated by MM cells or TNFalpha plus IL7 stimulation, can lead to downstream signaling involving NFkappaB and p38 MAPK. Inhibition of the p62-ZZ domain by XRK3F2 prevents transcriptional repression of the Runx2 gene by GFI1, thereby promoting osteoblastogenesis.

In summary, p62 (SQSTM1) appears to have multiple roles and interactions in cellular processes such as autophagy, EMT, fibrosis, mitophagy, and osteoblastogenesis. It is involved in response to oxidative and proteotoxic stress, and its dysregulation may contribute to age-related lung injuries and other pathological conditions. Further research is needed to fully understand the mechanisms and potential therapeutic implications of p62/SQSTM1 in these processes.

Protein Name: Sequestosome 1

Functions: Autophagy receptor required for selective macroautophagy (aggrephagy) (PubMed:34471133, PubMed:16286508, PubMed:20168092, PubMed:24128730, PubMed:28404643, PubMed:22622177). Functions as a bridge between polyubiquitinated cargo and autophagosomes (PubMed:34471133). Interacts directly with both the cargo to become degraded and an autophagy modifier of the MAP1 LC3 family (PubMed:16286508, PubMed:20168092, PubMed:24128730, PubMed:28404643, PubMed:22622177). Along with WDFY3, involved in the formation and autophagic degradation of cytoplasmic ubiquitin-containing inclusions (p62 bodies, ALIS/aggresome-like induced structures). Along with WDFY3, required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed:24128730, PubMed:20168092). Also involved in autophagy of peroxisomes (pexophagy) in response to reactive oxygen species (ROS) by acting as a bridge between ubiquitinated PEX5 receptor and autophagosomes (PubMed:26344566). May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. Adapter that mediates the interaction between TRAF6 and CYLD (By similarity). May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102). Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed:29496741). Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: interaction inactivates the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes (PubMed:20452972, PubMed:28380357, PubMed:33393215). Sequesters tensin TNS2 into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal degradation (PubMed:25101860)

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