The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy

Abstract

Signaling, proliferation, and inflammation are dependent on K63-linked ubiquitination—conjugation of a chain of ubiquitin molecules linked via lysine 63. However, very little information is currently available about how K63-linked ubiquitination is subverted in cancer. The present study provides, for the first time, evidence that cadmium (Cd), a widespread environmental carcinogen, is a potent activator of K63-linked ubiquitination, independently of oxidative damage, activation of ubiquitin ligase, or proteasome impairment. We show that Cd induces the formation of protein aggregates that sequester and inactivate cylindromatosis (CYLD) and selective autophagy, two tumor suppressors that deubiquitinate and degrade K63-ubiquitinated proteins, respectively. The aggregates are constituted of substrates of selective autophagy—SQSTM1, K63-ubiquitinated proteins, and mitochondria. These protein aggregates also cluster double-membrane remnants, which suggests an impairment in autophagosome maturation. However, failure to eliminate these selective cargos is not due to alterations in the general autophagy process, as degradation of long-lived proteins occurs normally. We propose that the simultaneous disruption of CYLD and selective autophagy by Cd feeds a vicious cycle that further amplifies K63-linked ubiquitination and downstream activation of the NF-κB pathway, processes that support cancer progression. These novel findings link together impairment of selective autophagy, K63-linked ubiquitination, and carcinogenesis.

TRIM14 inhibits OPTN-mediated autophagic degradation of KDM4D to epigenetically regulate inflammation

“…Numerous studies have shown that polyubiquitin chains are recognition signals for cargo receptors ( 23 ). Unlike the proteasomal pathway, where K48-linked ubiquitin chains serve as a major degradation signal, we and other groups have shown that polyubiquitin chains of other lineages can also be recognized by cargo receptors for autophagic degradation ( 9 , 11 , 31 – 33 ). K63-linked ubiquitination was originally reported as a nondegradation signal that mediated the activation of signaling cascades in innate immunity ( 34 , 35 ).…”

Blockage of Akt activation suppresses cadmium-induced renal tubular cellular damages through aggrephagy in HK-2 cells

“…We observed that cadmium exposure induced accumulation of ubiquitinated proteins and aggresome formation in HK-2 cells, RPTECs, and RPTEC/TERT1, another human proximal tubular cell line (data not shown). It has been reported that cadmium exposure does not affect proteasome activity 51 , 52 . Cadmium exposure induces protein misfolding and aggregation by binding to the thiol groups of cysteine residues in cells 37 .…”

Cardiac physiology and metabolic gene expression during late organogenesis among F. heteroclitus embryo families from crosses between pollution-sensitive and -resistant parents

“…The alterations of phosphatidylinositol phosphorylation (three genes) and ubiquitination (two genes) are interesting, since both are critical cellular regulation pathways implicated in PAH-induced carcinogenicity [86][87][88][89][90]. Considering the observed developmental delays in sensitive embryos exposed to polluted sediments (Fig.…”