Molecule Information

General Information of the Molecule (ID: Mol04400)

• Name: Sequestosome-1 ,Homo sapiens
• Synonyms: EBI3-associated protein of 60 kDa ; Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa ; Ubiquitin-binding protein p62
• Molecule Type: Protein
• Gene ID: 8878
• Sequence:
  MASLTVKAYLLGKEDAAREIRRFSFCCSPEPEAEAEAAAGPGPCERLLSRVAALFPALRP
  GGFQAHYRDEDGDLVAFSSDEELTMAMSYVKDDIFRIYIKEKKECRRDHRPPCAQEAPR
  N MVHPNVICDGCNGPVVGTRYKCSVCPDYDLCSVCEGKGLHRGHTKLAFPSPFGHLSEG
  FS HSRWLRKVKHGHFGWPGWEMGPPGNWSPRPPRAGEARPGPTAESASGPSEDPSVNFL
  KNV GESVAAALSPLGIEVDIDVEHGGKRSRLTPVSPESSSTEEKSSSQPSSCCSDPSKP
  GGNV EGATQSLAEQMRKIALESEGRPEEQMESDNCSGGDDDWTHLSSKEVDPSTGELQS
  LQMPE SEGPSSLDPSQEGPTGLKEAALYPHLPPEADPRLIESLSQMLSMGFSDEGGWLT
  RLLQTK NYDIGAALDTIQYSKHPPPL
• Function: Molecular adapter required for selective macroautophagy by acting as a bridge between polyubiquitinated proteinsand autophagosomes . Promotes therecruitment of ubiquitinated cargo proteins to autophagosomes viamultiple domains that bridge proteins and organelles in different steps. SQSTM1 first mediates the assembly and removal ofubiquitinated proteins by undergoing liquid-liquid phase separationupon binding to ubiquitinated proteins via its UBA domain, leading tothe formation of insoluble cytoplasmic inclusions, known as p62 bodies.SQSTM1 then interacts with ATG8 family proteins on autophagosomes viaits LIR motif, leading to p62 body recruitment to autophagosomes,followed by autophagic clearance of ubiquitinated proteins. SQSTM1 is itselfdegraded along with its ubiquitinated cargos . Also required to recruitubiquitinated proteins to PML bodies in the nucleus .Also involved in autophagy of peroxisomes in response toreactive oxygen species by acting as a bridge betweenubiquitinated PEX5 receptor and autophagosomes . Actsas an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1:interaction inactivates the BCR complex by sequestering thecomplex in inclusion bodies, promoting nuclear accumulation ofNFE2L2/NRF2 and subsequent expression of cytoprotective genes.Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 toautophagosomes . Involved in endosome organization byretaining vesicles in the perinuclear cloud: following ubiquitinationby RNF26, attracts specific vesicle-associated adapters, forming amolecular bridge that restrains cognate vesicles in the perinuclearregion and organizes the endosomal pathway for efficient cargotransport . Sequesters tensin TNS2into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomaldegradation . May regulate the activation of NFKB1 byTNF-alpha, nerve growth factor and interleukin-1. May play a role in titin/TTNdownstream signaling in muscle cells . Adapter thatmediates the interaction between TRAF6 and CYLD .{ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:10356400,ECO:0000269|PubMed:10747026, ECO:0000269|PubMed:11244088,ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:15340068,ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:15911346,ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16079148,ECO:0000269|PubMed:16286508, ECO:0000269|PubMed:17580304,ECO:0000269|PubMed:19931284, ECO:0000269|PubMed:20168092,ECO:0000269|PubMed:20452972, ECO:0000269|PubMed:22017874,ECO:0000269|PubMed:22622177, ECO:0000269|PubMed:24128730,ECO:0000269|PubMed:25101860, ECO:0000269|PubMed:26344566,ECO:0000269|PubMed:27368102, ECO:0000269|PubMed:28380357,ECO:0000269|PubMed:28404643, ECO:0000269|PubMed:29343546,ECO:0000269|PubMed:29496741, ECO:0000269|PubMed:29507397,ECO:0000269|PubMed:31857589, ECO:0000269|PubMed:33393215,ECO:0000269|PubMed:33472082, ECO:0000269|PubMed:33509017,ECO:0000269|PubMed:34471133, ECO:0000269|PubMed:34893540,ECO:0000269|PubMed:35831301, ECO:0000269|PubMed:37306101,ECO:0000269|PubMed:37802024}.
• Uniprot ID: SQSTM_HUMAN
• Ensembl ID: ENSG0000016101120
• HGNC ID: HGNC:11280

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [1]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: A2780/DDP cells; Ovarian; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: As western blotting revealed, A2780/DDP cells exhibited lower p62 protein level and higher LC3 II/I ratio than parental A2780 cells, indicating that autophagy was enhanced in DDP-resistant OC cells

Oxaliplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0] [2]

• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Resistant Drug: Oxaliplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MiaPaCa-2 cells; Blood; Homo sapiens (Human); CVCL_0428
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: Cell viability assay; Annexin V/PI flow cytometry assay
• Mechanism Description: A common characteristic among pancreatic cancer patients is the biomechanically altered tumor microenvironment (TME), which among others is responsible for the elevated mechanical stresses in the tumor interior. Although significant research has elucidated the effect of mechanical stress on cancer cell proliferation and migration, it has not yet been investigated how it could affect cancer cell drug sensitivity. Here, we demonstrated that mechanical stress triggers autophagy activation, correlated with increased resistance to oxaliplatin treatment in pancreatic cancer cells.

References

• Ref 1: Salidroside overcomes cisplatin resistance in ovarian cancer via the inhibition of CRNDE-mediated autophagy. Mol Cell Biochem. 2025 May;480(5):3097-3116.
• Ref 2: Mechanical forces inducing oxaliplatin resistance in pancreatic cancer can be targeted by autophagy inhibition. Commun Biol. 2024 Nov 27;7(1):1581.