Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma

被引：0

作者：

Nishimura, Sadaaki ^{[1
,2
]}

Linares, F. Juan ^{[1
,2
]}

L'Hermitte, Antoine ^{[3
]}

Duran, Angeles ^{[1
,2
]}

Cid-Diaz, Tania ^{[1
,2
]}

Martinez-Ordonez, Anxo ^{[1
,2
]}

Ruiz-Martinez, Marc ^{[1
,2
]}

Kudo, Yotaro ^{[3
]}

Marzio, Antonio ^{[1
,2
]}

Heikenwalder, Mathias ^{[4
,5
]}

Roberts, Lewis R. ^{[6
]}

Diaz-Meco, Maria T. ^{[1
,2
]}

Moscat, Jorge ^{[1
,2
]}

机构：

[1] Weill Cornell Med, Dept Pathol & Lab Med, New York, NY 10065 USA

[2] Weill Cornell Med, Edward Meyer Canc Ctr, New York, NY 10065 USA

[3] Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA 92037 USA

[4] German Canc Res Ctr Heidelberg DKFZ, Div Chron Inflammat & Canc, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[5] Univ Tubingen, Inst Interdisciplinary Res Canc Metab & Chron Inf, Fac Med, Res Ctr Malignome Metab & Microbiome M3, Otfried Muller Str 37, D-72076 Tubingen, Germany

[6] Mayo Clin, Canc Ctr, Div Gastroenterol & Hepatol, Coll Med & Sci, Rochester, MN 55905 USA

来源：

MOLECULAR CELL | 2024年 / 84卷 / 23期

基金：

美国国家卫生研究院;

关键词：

LIVER-CANCER; INFLAMMATION; IMMUNITY; CARCINOGENESIS; ACTIVATION; SENESCENCE; PROTEIN; MTORC1;

D O I：

10.1016/j.molcel.2024.09.026

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Hepatocellular carcinoma (HCC) emerges from chronic inflammation, to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that p62 activates the interferon (IFN) cascade by promoting STING ubiquitination by tripartite motif protein 32 (TRIM32) in HSCs. p62, binding neighbor of BRCA1 gene 1 (NBR1) and STING, triggers the IFN cascade by displacing NBR1, which normally prevents the interaction of TRIM32 with STING and its subsequent activation. Furthermore, NBR1 also antagonizes STING by promoting its trafficking to the endosome-lysosomal compartment for degradation independent of autophagy. Of functional relevance, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs by rescuing the inhibited STING-IFN pathway, thus enhancing anti-tumor responses mediated by CD8+ T cells. Therefore, NBR1 emerges as a synthetic vulnerability of p62 deficiency in HSCs by promoting the STING/IFN pathway, which boosts anti-tumor CD8+ T cell responses to restrain HCC progression.

引用

页码：4660 / 4676.e10

页数：28

共 69 条

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