MLN51 triggers P-body disassembly and formation of a new type of RNA granules

Abstract

Metastatic lymph node 51 (MLN51, also known as CASC3) is a core component of the exon junction complex (EJC), which is loaded onto spliced mRNAs and plays an essential role in determining their fate. Unlike the three other EJC core components [eIF4AIII, Magoh and Y14 (also known as RBM8A)], MLN51 is mainly located in the cytoplasm, where it plays a key role in the assembly of stress granules. In this study, we further investigated the cytoplasmic role of MLN51. We show that MLN51 is a new component of processing bodies (P-bodies). When overexpressed, MLN51 localizes in novel small cytoplasmic foci. These contain RNA, show directed movements and are distinct from stress granules and P-bodies. The appearance of these foci correlates with the process of P-body disassembly. A similar reduction in P-body count is also observed in human HER2-positive (HER2 + ) breast cancer cells overexpressing MLN51. This suggests that P-body disassembly and subsequent mRNA deregulation might correlate with cancer progression.

Function and Pathological Implications of Exon Junction Complex Factor Y14

“…The EJC core may assemble onto transcripts undergoing splicing in perispeckles [ 32 ]. In the cytoplasm, neither Y14-Magoh nor eIF4AIII is enriched in particular RNA granules, stress granules, or processing bodies (P-bodies) [ 21 , 33 ]. P-bodies are cytoplasmic foci containing translationally silenced mRNAs that are subject to degradation or reenter the translating pool [ 34 ].…”

“…EJCs and SR proteins multimerize to promote packaging and compaction of spliced mRNAs and subsequent mRNA biogenesis steps [ 17 ]. In addition, individual EJC components can also exert distinct and EJC-independent functions in various cellular processes [ 18 , 19 , 20 , 21 ]. Furthermore, some genetic diseases are associated with mutations in the genetic loci encoding the EJC components [ 22 ].…”

Overexpression of mRNA‑decapping enzyme 1a affects survival rate in colorectal carcinoma

“…mRNA-decapping enzyme 1a (DCP1a) is a cofactor involved in the removal of the 5'-methylguanosine cap from eukaryotic mRNAs, and may be used as a marker to analyze cellular processing bodies (P-bodies; PB) (8,9). P-bodies are one of the most well understood types of RNA granules, and are associated with a variety of diseases, including cancer (10,11). Certain PB-associated proteins have been implicated in cancer cell physiology and may be involved in tumorigenesis (10)(11)(12)(13)(14).…”

“…P-bodies are one of the most well understood types of RNA granules, and are associated with a variety of diseases, including cancer (10,11). Certain PB-associated proteins have been implicated in cancer cell physiology and may be involved in tumorigenesis (10)(11)(12)(13)(14). The effects of the expression of DCP1a on the prognosis of colorectal carcinoma remain unclear.…”

RNA Degradation in Neurodegenerative Disease

“…Once transferred, the mRNA is no longer translated [189,191] and is instead degraded by decapping enzymes [192,193] or other nucleases. However, mRNAs may also escape P-bodies and resume translation [187,194], and regulated expression of proteins such as NoBody and MLN51 can drive P-body disassembly [195,196]. Together, these observations indicate that P-bodies are part of a highly dynamic process characterized by constant flux between pools of mRNA transcripts that are being actively translated, those that are stalled or sequestered in SGs, and those that are being degraded within P-bodies.…”