Golgi-associated TRAF6 as a regulator of protein convertase FURIN for insulin receptor precursor processing

TY - JOUR

T1 - Golgi-associated TRAF6 as a regulator of protein convertase FURIN for insulin receptor precursor processing

AU - Liu, Minjun

AU - Zhou, Kun

AU - Sheng, Yang

AU - Zhang, Wen

AU - Chen, Qiaoli

AU - Chen, Ziyue

AU - Yang, Xinyu

AU - Jin, Yuxin

AU - Liu, Fangtong

AU - Mu, Yinqiu

AU - Su, Shu

AU - Feng, Weikuan

AU - Rong, Ping

AU - Wang, Juan

AU - Cohen, Philip

AU - Liang, Hui

AU - Zhao, Tong Jin

AU - Chen, Shuai

AU - Wang, Hong Yu

N1 - Copyright: © Science China Press 2025.

PY - 2025/12

Y1 - 2025/12

N2 - Obesity is a major pathological factor that induces insulin resistance and consequent type 2 diabetes through multiple mechanisms. Inactivation of the insulin receptor (INSR) contributes to the development of insulin resistance, whose protein level is down-regulated in obesity through as yet-undefined mechanisms. Here we show that the E3-ligase TRAF6 is a critical regulator of INSR maturation, whose inactivation prevents palmitic acid- or high-fat diet-induced diminution of the INSR. Consequently, genetic inactivation of TRAF6 enhances insulin signaling that further increases muscle glucose uptake and inhibits hepatic gluconeogenesis. TRAF6 inactivation increases the proprotein convertase FURIN that controls the processing of pro-INSR to mature INSR. Mechanistically, TRAF6 associates with the Golgi apparatus, where it ubiquitinates the cytosolic tail of FURIN, leading to its lysosomal degradation. This TRAF6-FURIN axis also regulates cholesterol metabolism via PCSK9 processing in the circulation. Collectively, our results reveal a critical role of TRAF6 in regulating proprotein processing and have therapeutic implications for metabolic control.

AB - Obesity is a major pathological factor that induces insulin resistance and consequent type 2 diabetes through multiple mechanisms. Inactivation of the insulin receptor (INSR) contributes to the development of insulin resistance, whose protein level is down-regulated in obesity through as yet-undefined mechanisms. Here we show that the E3-ligase TRAF6 is a critical regulator of INSR maturation, whose inactivation prevents palmitic acid- or high-fat diet-induced diminution of the INSR. Consequently, genetic inactivation of TRAF6 enhances insulin signaling that further increases muscle glucose uptake and inhibits hepatic gluconeogenesis. TRAF6 inactivation increases the proprotein convertase FURIN that controls the processing of pro-INSR to mature INSR. Mechanistically, TRAF6 associates with the Golgi apparatus, where it ubiquitinates the cytosolic tail of FURIN, leading to its lysosomal degradation. This TRAF6-FURIN axis also regulates cholesterol metabolism via PCSK9 processing in the circulation. Collectively, our results reveal a critical role of TRAF6 in regulating proprotein processing and have therapeutic implications for metabolic control.

KW - FURIN

KW - insulin receptor

KW - insulin sensitivity

KW - proprotein processing

KW - TRAF6

KW - ubiquitination

UR - https://www.scopus.com/pages/publications/105019573672

U2 - 10.1007/s11427-025-2957-9

DO - 10.1007/s11427-025-2957-9

M3 - Article

C2 - 41136690

AN - SCOPUS:105019573672

SN - 1674-7305

VL - 68

SP - 3617

EP - 3632

JO - Science China Life Sciences

JF - Science China Life Sciences

IS - 12

ER -