Sqstm1, also known as p62, is a multifunctional scaffolding protein that serves as a crucial adaptor in selective autophagy, a process of degrading specific organelles and protein aggregates [1,2]. It is involved in regulating various signaling pathways and is essential for maintaining cellular proteostasis [1,2,6]. In selective autophagy, it tags cytoplasmic components, often those ubiquitinated, for degradation in autophagosomes [1].

In vascular smooth muscle cells (VSMCs), Sqstm1 deficiency mimicked the phenotype of Ppargc1a depletion, presenting reduced autophagy and increased senescence both in vitro and in vivo, suggesting that Ppargc1a upregulates autophagy and reduces senescence through a Sqstm1-dependent mechanism [3]. In the liver, Sqstm1-knockout mice showed compromised protection against lipotoxicity, as Sqstm1 activates the non-canonical KEAP1-NFE2L2 pathway under lipotoxic conditions [4]. Also, disrupting the TRIB3-Sqstm1 interaction in mouse models of hepatic fibrosis restored autophagic flux and alleviated fibrosis [5].

In conclusion, Sqstm1 is a key player in selective autophagy, regulating various cellular processes. Gene-knockout mouse models, such as those of Sqstm1 in VSMCs, liver, and in hepatic fibrosis models, have revealed its importance in autophagy-related processes and disease conditions like vascular senescence, non-alcoholic fatty liver disease, and hepatic fibrosis. Understanding Sqstm1's functions provides insights into disease mechanisms and potential therapeutic strategies for these conditions.

References:

1. Lamark, Trond, Svenning, Steingrim, Johansen, Terje. 2017. Regulation of selective autophagy: the p62/SQSTM1 paradigm. In Essays in biochemistry, 61, 609-624. doi:10.1042/EBC20170035. https://pubmed.ncbi.nlm.nih.gov/29233872/

2. Jeong, Se-Jin, Zhang, Xiangyu, Rodriguez-Velez, Astrid, Evans, Trent D, Razani, Babak. 2019. p62/SQSTM1 and Selective Autophagy in Cardiometabolic Diseases. In Antioxidants & redox signaling, 31, 458-471. doi:10.1089/ars.2018.7649. https://pubmed.ncbi.nlm.nih.gov/30588824/

3. Salazar, Gloria, Cullen, Abigail, Huang, Jingwen, Forouzandeh, Farshad, Hwang, Hyun Seok. 2019. SQSTM1/p62 and PPARGC1A/PGC-1alpha at the interface of autophagy and vascular senescence. In Autophagy, 16, 1092-1110. doi:10.1080/15548627.2019.1659612. https://pubmed.ncbi.nlm.nih.gov/31441382/

4. Lee, Da Hyun, Park, Jeong Su, Lee, Yu Seol, Lee, Yong-Ho, Bae, Soo Han. 2020. SQSTM1/p62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity. In Autophagy, 16, 1949-1973. doi:10.1080/15548627.2020.1712108. https://pubmed.ncbi.nlm.nih.gov/31913745/

5. Zhang, Xiao-Wei, Zhou, Ji-Chao, Peng, Dian, Huang, Bo, Hu, Zhuo-Wei. 2019. Disrupting the TRIB3-SQSTM1 interaction reduces liver fibrosis by restoring autophagy and suppressing exosome-mediated HSC activation. In Autophagy, 16, 782-796. doi:10.1080/15548627.2019.1635383. https://pubmed.ncbi.nlm.nih.gov/31286822/

6. Kumar, Anita V, Mills, Joslyn, Lapierre, Louis R. 2022. Selective Autophagy Receptor p62/SQSTM1, a Pivotal Player in Stress and Aging. In Frontiers in cell and developmental biology, 10, 793328. doi:10.3389/fcell.2022.793328. https://pubmed.ncbi.nlm.nih.gov/35237597/