Journal of hepatology · 2024
Targeting PYK2 with heterobifunctional T6BP helps mitigate MASLD and MASH-HCC progression.
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Xu Minxuan, Zhao Junjie, Zhu Liancai, Ge Chenxu, Sun Yan, Wang Ranran, Li Yuanyuan, Dai Xianling, Kuang Qin, Hu Linfeng, Luo Jing, Kuang Gang, Ren Yanrong, Wang Bochu, Tan Jun, Shi Shengbin
Аннотация
BACKGROUND & AIMS: The mechanisms underlying the regulation of hepatocyte non-receptor tyrosine kinases in metabolic dysfunction-associated steatohepatitis (MASH) remain largely unclear.
METHODS: Hepatocyte-specific overexpression or deletion and anti-protein tyrosine kinase 2 beta (PYK2) or anti-TRAF6-binding protein (T6BP) crosslinking were utilized to study fatty liver protection by T6BP. A P-PTC (peptide-proteolysis targeting chimera) degrades PYK2 to block MASH progression.
RESULTS: We found that T6BP is a novel and critical suppressor of PYK2 that reduces hepatic lipid accumulation, pro-inflammatory factor release, and pro-fibrosis production. Mechanistic evidence suggests that T6BP directly targets PYK2 and prevents its N-terminal FERM domain-triggered dimerization, disrupting downstream PYK2-JNK signaling hyperactivation. Additionally, T6BP favorably recruits CBL, a particular E3 ubiquitin ligase targeting PYK2, to form a complex and degrade PYK2. T6BP (F1), a core fragment of T6BP, directly blocks N-terminal FERM domain-associated dimerization of PYK2, followed by T6BP-recruiting CBL-mediated PYK2 degradation in a typical T6BP-dependent manner when the tiny fragment is specifically expressed using thyroxine binding globulin (TBG) vectors. This inhibits the progression of MASH, MASH-related hepatocellular carcinoma, and metabolic syndrome in dietary rodent models. We devised, and validated in animal models, the first-ever P-PTC based on the core segment of T6BP, as a ligand for the targeted recruitment of CBL, that could be used to target metabolic disorders like MASH.
CONCLUSIONS: Our study uncovered a previously unknown mechanism, with T6BP identified as a key suppressor of steatosis. This, alongside the discovery of crucial T6BP-based fragments that interrupt PYK2 dimerization hold much promise for the treatment of MASH.
IMPACT AND IMPLICATIONS: Excessive high-energy diet ingestion is critical in driving steatohepatitis via regulation of hepatocyte non-receptor tyrosine kinases. The mechanisms underlying the regulation of hepatocyte PYK2 in metabolic dysfunction-associated steatohepatitis remain largely unclear. Here, we found that T6BP as a critical fatty liver eliminator could be used for the development of promising therapeutic options. Additionally, vital T6BP-based pharmacon fragments that impede PYK2 dimerization have been found, offering new and effective treatments for advanced fatty liver symptoms and complications.
METHODS: Hepatocyte-specific overexpression or deletion and anti-protein tyrosine kinase 2 beta (PYK2) or anti-TRAF6-binding protein (T6BP) crosslinking were utilized to study fatty liver protection by T6BP. A P-PTC (peptide-proteolysis targeting chimera) degrades PYK2 to block MASH progression.
RESULTS: We found that T6BP is a novel and critical suppressor of PYK2 that reduces hepatic lipid accumulation, pro-inflammatory factor release, and pro-fibrosis production. Mechanistic evidence suggests that T6BP directly targets PYK2 and prevents its N-terminal FERM domain-triggered dimerization, disrupting downstream PYK2-JNK signaling hyperactivation. Additionally, T6BP favorably recruits CBL, a particular E3 ubiquitin ligase targeting PYK2, to form a complex and degrade PYK2. T6BP (F1), a core fragment of T6BP, directly blocks N-terminal FERM domain-associated dimerization of PYK2, followed by T6BP-recruiting CBL-mediated PYK2 degradation in a typical T6BP-dependent manner when the tiny fragment is specifically expressed using thyroxine binding globulin (TBG) vectors. This inhibits the progression of MASH, MASH-related hepatocellular carcinoma, and metabolic syndrome in dietary rodent models. We devised, and validated in animal models, the first-ever P-PTC based on the core segment of T6BP, as a ligand for the targeted recruitment of CBL, that could be used to target metabolic disorders like MASH.
CONCLUSIONS: Our study uncovered a previously unknown mechanism, with T6BP identified as a key suppressor of steatosis. This, alongside the discovery of crucial T6BP-based fragments that interrupt PYK2 dimerization hold much promise for the treatment of MASH.
IMPACT AND IMPLICATIONS: Excessive high-energy diet ingestion is critical in driving steatohepatitis via regulation of hepatocyte non-receptor tyrosine kinases. The mechanisms underlying the regulation of hepatocyte PYK2 in metabolic dysfunction-associated steatohepatitis remain largely unclear. Here, we found that T6BP as a critical fatty liver eliminator could be used for the development of promising therapeutic options. Additionally, vital T6BP-based pharmacon fragments that impede PYK2 dimerization have been found, offering new and effective treatments for advanced fatty liver symptoms and complications.