Advances in the Structural and Physiological Functions of SHARPIN

Abstract

SHARPIN was initially found as a SHANK-associated protein. SHARPIN can be used as an important component to form the linear ubiquitin chain assembly complex (LUBAC) with HOIL-1L, HOIP to produce a linear ubiquitin chain connected N-terminal Met1, playing a critical role in various cellular processes including NF-κB signaling, inflammation, embryogenesis and apoptosis. SHARPIN alone can also participate in many critical physiological activities and cause various disorders such as chronic dermatitis, tumor, and Alzheimer’s disease. Mice with spontaneous autosomal recessive mutations in the SHARPIN protein mainly exhibit chronic dermatitis and immunodeficiency with elevated IgM. Additionally, SHARPIN alone also plays a key role in various cellular events, such as B cells activation and platelet aggregation. Structural studies of the SHARPIN or LUBAC have been reported continuously, advancing our understanding of it at the molecular level. However, the full-length structure of the SHARPIN or LUBAC was lagging, and the molecular mechanism underlying these physiological processes is also unclear. Herein, we summarized the currently resolved structure of SHARPIN as well as the emerging physiological role of SHARPIN alone or in LUBAC. Further structural and functional study of SHARPIN will provide insight into the role and underlying mechanism of SHARPIN in disease, as well as its potential application in therapeutic.

Unraveling the prognostic significance and molecular characteristics of tumor-infiltrating B lymphocytes in clear cell renal cell carcinoma through a comprehensive bioinformatics analysis

“…Its encoding protein was one of essential subunits to form the linear ubiquitin chain assembly complex (LUBAC) ( 48 , 49 ). Previous researches found there is a diminished activation of the IKK complex and NF-κB in B cells in mice with SHARPIN deficiency ( 49 ) and LUBAC could involve in B-cell activation by regulating CD40 signaling ( 50 ). Another report indicated knockdown of SHARPIN could inhibit ccRCC tumor growth in xenograft models ( 51 ).…”

The mechanism of linear ubiquitination in regulating cell death and correlative diseases

“…LUBAC is the only ubiquitin E3 ligase complex to date that has been found to function on linear ubiquitin chain. It is composed of three parts: the heme-oxidized IRP2 ubiquitin ligase 1 L (HOIL-1L, approximately 123 kDa, 91.2% amino acid sequence conservation between humans and mice) encoded by RanBP-type and C3HC4-type zinc finger containing 1 (RBCK1), HOIL-1 interacting protein (HOIP, the molecular weight at 58 kDa, 86.5% conservation) encoded by Ring finger protein 31 (RNF31), and Shank-associated RH-domain interacting protein (SHARPIN, about 40 kDa, 73.6% conservation) encoded by SHARPIN [ 5 , 17 , 18 ]. The HOIP belongs to the RBR family due to the RBR domain.…”