Reactome | p-S349 SQSTM1 oligomer binds KEAP1:CUL3:RBX1

p-S349 SQSTM1 oligomer binds KEAP1:CUL3:RBX1

Stable Identifier

R-HSA-9759169

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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p-S349 SQSTM1 oligomer binds KEAP1:CUL3:RBX1

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SQSTM1 binds to the KEAP1 subunit of the CRL3 ubiquitin ligase complex through the KEAP1 interacting region (KIR) located at residues 339-358 (Jain et al, 2010). Like NFE2L2, SQSTM1 has a KELCH1-domain binding STGE motif that is thought to interact with the KEAP1 complex in the 'open' conformation. Binding is enhanced by phosphorylation of the SQSTM1 STGE motif (Ichimura et al, 2013; reviewed in Baird and Yamamoto, 2020).
SQSTM1 is a transcriptional target of NFE2L2 and is upregulated in the presence of cellular stressors like reactive oxygen species (ROS) and electrophiles (reviewed in Baird and Yamamoto, 2020). Upregulation of SQSTM1 under stress conditions leads to competition between NFE2L2 and SQSTM1 for KEAP1 binding and results in stabilization of NFE2L2 protein levels. This establishes a positive feedback loop as NFE2L2 is able to translocate into the nucleus to promote expression of its target genes (Jain et al, 2010).
SQSTM1 has also been shown to be a substrate for KEAP1:CUL3:RBX1-mediated ubiquitination. Ubiquitination at lysine 420 increases the ability of SQSTM1 to sequester and degrade target ubiquitinated proteins through selective autophagy (Lee et al, 2017). Some evidence shows that in addition to competing with NFE2L2 for KEAP1-binding, SQSTM1 also targets KEAP1 for sequestration and degradation through the autophagy pathway (Copple et al, 2010; reviewed in Jiang et al, 2015). Sestrin proteins may also play a role in targeting KEAP1 for SQSTM1-dependent autophagy (Bae et al, 2013; Ro et al, 2014).

Literature References

PubMed ID	Title	Journal	Year
25040165	Sestrin2 promotes Unc-51-like kinase 1 mediated phosphorylation of p62/sequestosome-1 Lee, JH, Semple, IA, Ro, SH, Park, H, Park, H, Kim, M, Park, HW, Kim, JS	FEBS J	2014
20378532	Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway Layfield, R, Copple, IM, Goldring, CE, Foster, BJ, Park, BK, Obeng, AD, Jenkins, RE, Kitteringham, NR, Lister, A	J Biol Chem	2010
32284348	The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway Yamamoto, M, Baird, L	Mol Cell Biol	2020
23274085	Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage Lim, JM, Park, YN, Lee, HE, Sung, SH, Bae, SH, Kang, D, Oh, SY, Lee, SK, Rhee, SG	Cell Metab	2013
26117325	p62 links autophagy and Nrf2 signaling Rojo de la Vega, M, Zhang, DD, Chapman, E, Harder, B, Wong, PK, Jiang, T	Free Radic Biol Med	2015
24011591	Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy Motohashi, H, Saito, T, Komatsu, M, Lee, MS, Sou, YS, Takagi, K, Kouno, T, Ichimura, Y, Hirao, A, Hoshii, T, Ishimura, R, Hasegawa, J, Mizushima, T, Yang, Y, Yamamoto, M, Kageyama, S, Tanaka, K, Fukutomi, T, Waguri, S, Yoshimori, T	Mol Cell	2013
20452972	p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription Larsen, KB, Sjøttem, E, Awuh, JA, Jain, A, Lamark, T, Hayes, JD, Johansen, T, McMahon, M, Øvervatn, A	J Biol Chem	2010
28380357	Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination Weihl, CC, Chou, TF, Razani, B, Pittman, SK, Lee, Y, Keith, AL	Cell Rep	2017